Substituted arylpyrazines

ABSTRACT

Arylpyrazine compounds are provided, including arylpyrazines that can bind with high affinity and high selectivity to CRF 1  receptors, including human CRF 1  receptors. The invention thus includes methods for treatment of disorders and diseases associated with CRF 1  receptors, including CNS-related disorders and diseases, particularly affective disorders and diseases, and acute and chronic neurological disorders and diseases.

[0001] This application claims the benefit of U.S. ProvisionalApplication Serial No. 60/182,934 filed Feb. 16, 2000 and of U.S.Provisional Application Serial No. 60/206,455 filed May 22, 2000, theteachings of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to novel arylpyrazine compoundsthat have useful pharmacological properties in that they bind tocellular receptors, including CRF receptors. Certain of these compoundscan bind to and modulate the activity of such receptors. Importantly,the compounds of the invention include compounds that bind with highselectivity and/or high affinity to CRF1 receptors (CorticotropinReleasing Factor type 1 Receptors). This invention also relates topharmaceutical compositions comprising such compounds and to the use ofsuch compounds as pharmaceutical agents, e.g., in treatment ofpsychiatric disorders and neurological diseases, including majordepression, anxiety-related disorders, post-traumatic stress disorder,supranuclear palsy and feeding disorders, as well as treatment ofimmunological, cardiovascular or heart-related diseases and colonichypersensitivity associated with psychopathological disturbance andstress. Additionally this invention relates to the use such compounds asprobes for the localization of cellular receptors in tissue sections.

BACKGROUND OF THE INVENTION

[0003] Corticotropin releasing factor (CRF), a 41 amino acid peptide, isthe primary physiological regulator of proopiomelanocortin (POMC)derived peptide secretion from the anterior pituitary gland. In additionto its endocrine role at the pituitary gland, immunohistochemicallocalization of CRF has demonstrated that the hormone has a broadextrahypothalamic distribution in the central nervous system andproduces a wide spectrum of autonomic, electrophysiological andbehavioral effects consistent with a neurotransmitter or neuromodulatorrole in brain. There is also evidence that CRF plays a significant rolein integrating the response of the immune system to physiological,psychological, and immunological stressors.

[0004] Clinical data provide evidence that CRF has a role in psychiatricdisorders and neurological diseases including depression,anxiety-related disorders and feeding disorders. A role for CRF has alsobeen postulated in the etiology and pathophysiology of Alzheimer'sdisease, Parkinson's disease, Huntington's disease, progressivesupranuclear palsy and amyotrophic lateral sclerosis as they relate tothe dysfunction of CRF neurons in the central nervous system.

[0005] In affective disorder, or major depression, the concentration ofCRF is significantly increased in the cerebral spinal fluid (CSF) ofdrug-free individuals. Furthermore, the density of CRF receptors issignificantly decreased in the frontal cortex of suicide victims,consistent with a hypersecretion of CRF. In addition, there is a bluntedadrenocorticotropin (ACTH) response to CRF (i.v. administered) observedin depressed patients. Preclinical studies in rats and non-humanprimates provide additional support for the hypothesis thathypersecretion of CRF may be involved in the symptoms seen in humandepression. There is also preliminary evidence that tricyclicantidepressants can alter CRF levels and thus modulate the numbers ofCRF receptors in brain.

[0006] CRF has also been implicated in the etiology of anxiety-relateddisorders. CRF produces anxiogenic effects in animals and interactionsbetween benzodiazepine/non-benzodiazepine anxiolytics and CRF have beendemonstrated in a variety of behavioral anxiety models. Preliminarystudies using the putative CRF receptor antagonist-helical ovine CRF(9-41) in a variety of behavioral paradigms demonstrate that theantagonist produces “anxiolytic-like” effects that are qualitativelysimilar to the benzodiazepines. Neurochemical, endocrine and receptorbinding studies have all demonstrated interactions between CRF andbenzodiazepine anxiolytics providing further evidence for theinvolvement of CRF in these disorders. Chlordiazepoxide attenuates the“anxiogenic” effects of CRF in both the conflict test and in theacoustic startle test in rats. The benzodiazepine receptor antagonist Ro15-1788, which was without behavioral activity alone in the operantconflict test, reversed the effects of CRF in a dose-dependent manner,while the benzodiazepine inverse agonist FG 7142 enhanced the actions ofCRF.

[0007] CRF has also been implicated in the pathogeneisis of certainimmunological, cardiovascular or heart-related diseases such ashypertension, tachycardia and congestive heart failure, stroke andosteoporosis, as well as in premature birth, psychosocial dwarfism,stress-induced fever, ulcer, diarrhea, post-operative ileus and colonichypersensitivity associated with psychopathological disturbance andstress.

[0008] The mechanisms and sites of action through which conventionalanxiolytics and antidepressants produce their therapeutic effects remainto be fully elucidated. It has been hypothesized however, that they areinvolved in the suppression of CRF hypersecretion that is observed inthese disorders. Of particular interest are that preliminary studiesexamining the effects of a CRF receptor antagonist peptide (α-helicalCRF₉₋₄₁) in a variety of behavioral paradigms have demonstrated that theCRF antagonist produces “anxiolytic-like” effects qualitatively similarto the benzodiazepines.

[0009] Certain small molecule compounds for the treatment of CRF relateddisorders have been disclosed in the literature [for a review see J.McCarthy et al. Curr. Pharm. Des. 5:289 (1999)]. However, none of thesecompounds has an arylpyrazine structure.

[0010] Cox et al. (WO 98/38174) have disclosed certain aryl pyrazinederivatives for use as sodium channel blockers in the treatment ofcentral nervous system disorders. The Cox application requires that thearylpyrazine compounds be substituted with two-amino or amido groups.

SUMMARY OF THE INVENTION

[0011] We have now discovered novel arylpyrazine compounds, includingarylpyrazines that can bind with high affinity and high selectivity toCRF, receptors, including human CRF, receptors. The invention thusincludes methods for treatment of disorders and diseases associated withCRF, receptors, including CNS-related disorders and diseases,particularly affective disorders and diseases, and acute and chronicneurological disorders and diseases.

[0012] Arylpyrazine compounds of the invention are preferablysubstituted at the 2-ring position by a carbocyclic aryl group such asphenyl, naphthyl and the like, or a heteroaromatic group, particularly aheteroaromatic having a nitrogen ring member such as pyridyl,pyrimidinyl and the like. Arylpyrazine compounds of the invention alsoare preferably substituted at the 5-ring position (para with respect tothe aryl substituent) by a non-hydrogen substituent, particularly anon-aromatic group such as alkyl, alkenyl, alkynyl, heteroalkyl and thelike, preferably aminoalkyl and alkoxy. Preferably the 3-ring positionof pyrazine compounds of the invention is unsubstituted (i.e. hydrogen)or substituted by other than amino (—NH₂) or alkylamide (—NHC(═O)alkyl,particularly —NHC(═O)C₁₋₄alkyl or —NHC(═O)C₃₋₇cycloalkyl), and/or the5-ring position of pyrazine compounds of the invention are other thanhydrogen, alkyl, aminoalkyl or a nitrogen-containing heteroalicycliccompound.

[0013] Typically preferred compounds of the invention include those ofthe following Formula I:

[0014] wherein:

[0015] Ar is substituted phenyl, optionally substituted napthyl, or anoptionally substituted heterocyclic group having from 1 to 3 rings, and3 to 8 ring members in each ring and 1 to about 3 hetero atoms;

[0016] R₁ and R₃ are each independently hydrogen, halogen, cyano, nitro,amino, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted mono ordialkylamino, optionally substituted alkoxy, optionally substitutedalkylthio, optionally substituted alkylsulfinyl, or optionallysubstituted alkylsulfonyl; and

[0017] R₂ is halogen, cyano, nitro, amino, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted alkylamino, optionally substituted alkoxy,optionally substituted alkylthio, optionally substituted alkylsulfinyl,or optionally substituted alkylsulfonyl;

[0018] with the proviso that if Ar is phenyl substituted with halogen,napthyl, or naphthyl substituted with halogen, then the compounds whereR₃ is hydrogen or amino are excluded.

[0019] Preferred compounds of the invention also include those of thefollowing Formula IA:

[0020] or a pharmaceutically acceptable salt thereof, wherein:

[0021] R₁ is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halogen, CN, C₁₋₄ haloalkyl, trifluoromethyl, trifluoromethoxy, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), and S(O)_(n)(C₁₋₄alkyl);

[0022] R₂ is selected from the group consisting of —XR_(A) and Y,wherein —X, R_(A), and Y are defined below; and

[0023] R₃ is selected from the group consisting of hydrogen, halogen,C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl),and —S(O)_(n)(C₁₋₄ alkyl), haloalkyl, trifluoromethyl, trifluoromethoxy,—XR_(A) and Y;

[0024] R₄ is absent or an oxygen atom;

[0025] Ar is phenyl, mono-, di-, or tri-substituted with R_(C), or

[0026] Ar is selected from the group consisting of:

[0027] naphthyl, pyridyl, pyridonyl, pyrimidinyl, and thiophenyl, eachof which is unsubstituted or mono-, di-, or tri-substituted with R_(C);

[0028] with the proviso that if Ar is phenyl substituted with halogen,napthyl, or naphthyl substituted with halogen, then the compounds whereR₃ is hydrogen are excluded;

[0029] R_(A) and R_(B), which may be the same or different, areindependently selected at each occurrence from the group consisting of:hydrogen and straight, branched, or cyclic alkyl groups consisting of 1to 8 carbon atoms, which may contain one or more double or triple bonds,each of which may be further substituted with one or more substituent(s)selected from oxo, hydroxy, halogen, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —N(C₁₋₄alkyl)C(═O)(C₁₋₄ alkyl), —NHS(O),(C₁₋₄ alkyl), —S(O),(C₁₋₄ alkyl),—S(O),NH(C₁₋₄ alkyl), —S(O),N(C₁₋₄ alkyl)(C₄ alkyl), and Z;

[0030] R_(C) is independently selected at each occurrence from the groupconsisting of halogen, cyano, haloalkyl, trifluoromethyl,trifluoromethoxy, hydroxy, amino, and C₁₋₆ alkyl optionally substitutedwith 0-2 R_(D), C₂ ₆ alkenyl substituted with 0-2 R_(D), C₁₋₄ alkynylsubstituted with 0-2 R_(D), C₃₋₇ cycloalkyl substituted with 0-2 R_(D),(C₃₋₇ cycloalkyl)C₁₋₄ alkyl substituted with 0-2 R_(D), —O(C₁₋₄ alkyl)substituted with 0-2 R_(D), —NH(C₁₋₄ alkyl) substituted with 0-2 R_(D),—N(C₁₋₄ alkyl)(C₁₋₄ alkyl) each independently substituted with 0-2R_(D), —XR_(A), and Y;

[0031] R_(D) is independently selected at each occurrence the groupconsisting of halogen, hydroxy, cyano, C₁₋₄alkyl, —O(C₁₋₄alkyl),—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), morpholino, pyrrolidino,piperidino, thiomorpholino, piperazino, 4-hydroxypiperidino,—S(O),(C₁₋₄alkyl), trifluoromethyl, trifluoromethoxy, CO(C₁₋₄alkyl),CONH(C₁₋₄alkyl), CON(C₁₋₄alkyl)(C₁₋₄alkyl), —XR_(A), and Y;

[0032] X is independently selected at each occurrence from the groupconsisting of —CH₂—, —CHR_(B)—, —O—, —C(═O)—, —C(═O)O—, —S(O)_(n)-,—NH—, —NR_(B)—, —C(═O)NH-, —C(═O)NR_(B)—, —S(O)NH—, —S(O)_(n)NR_(B)—,—OC(═S)S—, —NHC(═O)—, —NR_(B)C(═O)—, —NHS(O)_(n)-,—OSiH_(n)(C₁₋₄alkyl)_(2-n)-, and —NR_(B)S(O)_(n)-; and

[0033] Y and Z are independently selected at each occurrence from thegroup consisting of: 3- to 7-membered carbocyclic and heterocyclicgroups, which are saturated, unsaturated, or aromatic, which may besubstituted with one or more substituents selected from halogen,haloalkyl, oxo, hydroxy, amino, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), and —S(O),(C₁₋₄ alkyl), and said 3-to 7-membered heterocyclic groups contain one or more heteroatom(s)selected from N, 0, and S, with the point of attachment being eithercarbon or nitrogen; and

[0034] n is independently selected at each occurrence from 0, 1, and 2.

[0035] Particularly preferred arylpyrazines of the invention includecompounds of the following Formula IB:

[0036] wherein:

[0037] Ar is selected from the group consisting of phenyl, 1- or2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, each Aroptionally substituted with 1 to 5 with R₆ group, with the proviso thatat least one of the positions ortho or para to the point of attachmentof Ar to the pyrazine ring system is substituted;

[0038] R₁ is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂ ₄ alkynyl,(C₃₋₆ cycloalkyl)C₁₋₄ alkyl, halogen, CN, C₁₋₄ haloalkyl, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), and —S(O)_(b)(C₁₋₄alkyl), wherein b is 0, 1, or 2;

[0039] R₂ is selected from the group consisting of —XR₄ and Y, whereinX, R₄, and Y are as defined below;

[0040] X is independently selected at each occurrence from the groupconsisting of —CH₂—, —CHR₅—, —O—, —S(O)_(n)-, —NH—, —NR₅—, —C(═O)NH—,—C(═O)NR₅—, —S(O),NH—, —S(O),NR₅—, —NHC(═O)—, —NR₅C(═O)—, —NHS(O)_(n)-,and —NR₅S(O)_(n)- (where n is 0, 1, or 2);

[0041] Y and Z are independently selected at each occurrence from thegroup consisting of:

[0042] 3- to 7-membered heterocycles, saturated or unsaturated,containing one or more heteroatom(s) selected from N, O, and S, with thepoint of attachment being either carbon or nitrogen (where applicable),and which may be further substituted with one or more substituentsselected from halogen, oxo, hydroxy, amino, C₁₋₄ alkyl, —O(C₁₋₄ alkyl),—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), and —S(O)_(a)(C₁₋₄ alkyl)(wherein a is 0, 1, or 2);

[0043] R₃ is selected from the group consisting of hydrogen, halogen,C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl),and —S(O),(C₁₋₄ alkyl) (wherein c is 0, 1, or 2), trifluoromethyl,trifluoromethoxy, —XR₄, and Y, where —X, R₄, and Y are as defined above.

[0044] R₄ and R₅, which may be the same or different, are independentlyselected at each occurrence from the group consisting of:

[0045] hydrogen, straight, branched, or cyclic alkyl groups consistingof 1 to 8 carbon atoms, which may contain one or more double or triplebonds, each of which may optionally be further substituted with one ormore substituent(s) selected from oxo, hydroxy, —O(C₁₋₄ alkyl), —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —N(C₁₋₄alkyl)C(O)(C₁₋₄ alkyl), —NHS(O)_(m)(C₁₋₄ alkyl), —S(O)_(m)(C₁₋₄ alkyl),—S(O),NH(C₄ alkyl), —S(O)_(m)N(C₁₋₄ alkyl)(C₁₋₄ alkyl), (where m is 0,1, or 2), and Z, wherein Z is as defined above;

[0046] R₆ is independently selected at each occurrence from halogen,trifluoromethyl, trifluoromethoxy, hydroxy, amino, and Cl-C₆ alkyl(optionally substituted with 0-2 R₇, C₂₋₆ alkenyl substituted with 0-2R₇, C₁₋₄ alkynyl substituted with 0-2 R₇, C₃₋₆ cycloalkyl substitutedwith 0-2 R₇, (C₃₋₆ cycloalkyl)C₁₋₄ alkyl substituted with 0-2 R₇, O(C₁₋₄alkyl) substituted with 0-2 R₇, —NH(C₁₋₄ alkyl) substituted with 0-2 R₇,—N(C₁₋₄ alkyl)(C₁₋₄ alkyl) each independently substituted with 0-2 R₇,—XR₄, cyano, and Y; and

[0047] R₇ is independently selected at each occurrence the groupconsisting of halogen, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)(C₁₋₄ alkyl), morpholino, pyrrolidino, piperidino,thiomorpholino, piperazino, 4-hydroxypiperidino, —S(O),(C₁₋₄ alkyl),trifluoromethyl, trifluoromethoxy, CO(C₁₋₄alkyl), CONH(C₁₋₄alkyl),CON(C₁₋₄alkyl)(C₁₋₄alkyl), —XR₄ and Y, wherein X, R₄ and Y are definedas above and p is 0, 1 or 2;

[0048] and pharmaceutically acceptable salts thereof;

[0049] and preferably if Ar is phenyl substituted with halogen,naphthyl, or naphthyl substituted with halogen, then the exclusion ofcompounds where 1) R₃ being hydrogen, amino (—NH₂) or alkylamideparticularly —NHC(═O)C₁₋₄alkyl or —NHC(═O)C₃,₇cycloalkyl, and/or 2) R₂being hydrogen, alkylamide particularly

[0050] —NHC(═O)C₁₋₄alkyl or —NHC(═O)C₃₋₇cycloalkyl, amino substituted byone or two alkyl particularly C₁₋₄ alkyl, or a nitrogen-containing6-membered ring.

[0051] In the above Formulae I, IA, and IB, as well as below-specifiedFormulae Ia through Ie, II, IIa through IIi, III, IIIa through IIIe andIV, preferred Ar groups include 2,4-dichlorophenyl, 2,4-dimethoxyphenyl,4-methoxy-2-methylphenyl, 2,4,6-trimethylphenyl,4-methoxy-2,6-dimethylphenyl, 4-cyano-2,6-dimethylphenyl,2-methoxy-4,6-dimethylphenyl, 2-methoxy-4,6-bis(trifluoromethyl)phenyl,2,6-dichloro-4-methoxyphenyl,2-(2-(1-morpholino)ethoxy)-4,6-dimethylphenyl,2-(2-(4-hydroxy-1-piperidino)ethoxy)-4,6-dimethylphenyl,2-methyl-4-(dimethylamino)-3-pyridyl, and2-chloro-4-dimethylamino-3-pyridyl, 2-methoxy-4,6-dimethyl-3-pyridyl.

[0052] In the above Formulae I, IA, and IB, as well as below-specifiedFormulae Ia through Ie, II, IIa through IIi, III, IIIa through IIIe andIV, preferred R₁ groups include methyl, ethyl, chloro, bromo, iodo,trifluoromethyl, methoxy, dimethylamino, and thiomethoxy.

[0053] In the above Formulae I, IA, and IB, as well as below-specifiedFormulae Ia through Ie, II, IIa through IIi, III, IIIa through IIIe andIV, preferred R₂ groups include dipropylamino, bis(2-methoxyethyl)amino,4-methyl-1-piperazino, 3-pentylamino, 4-heptylamino,1,3-dimethoxy-2-propylamino, 1-(dimethylamino)-2-pentylamino,1-(3-pyridyl)-2-butylamino, (2-methoxy-5-pyridine)amino, 3-pentyloxy,4-heptyloxy, 1-methoxy-2-butyloxy, and 1,3-dimethoxy-2-propyloxy.

[0054] In the above Formulae I, IA, and IB, as well as below-specifiedFormulae Ia through Ie, II, IIa through IIi, III, IIIa through IIIe andIV, preferred R₃ groups include methyl, ethyl, chloro, trifluoromethyl,methoxy, dimethylamino, thiomethoxy, methanesulfonyl,(1-morpholino)methyl, 2-(1-pyrrolidino)ethyl, and (2-methoxy)ethoxy.

[0055] Preferred arylpyrazines of the invention exhibit good activity ina standard in vitro CRF receptor binding assays, specifically the assayas specified in Example 96 which follows. Particularly preferredarylpyrazines of the invention have an IC₅₀ in such a defined standardin vitro CRF receptor binding assay of about 1.5 micromolar or less,still more preferably an IC₅₀ of about 100 nanomolar or less, or evenmore preferably an IC₅₀ of about 10 nanomolar or less or even 1nanomolar or less in a such a defined standard in vitro CRF receptorbinding assay.

[0056] Preferred arylpyrazines of the invention do not show activity ina standard in vitro Na channel functional assay, specifically the assayas specified in Example 99 which follows. Particularly preferredarylpyrazines of the invention do not show any statistically significantactivity in a defined standard in vitro Na channel functional assay 0 atthe p<0.05 level of significance.

[0057] The invention further comprises methods of treating patientssuffering from or susceptible to (i.e. prophylactic treatment) certaindisorders or diseases with an effective amount of a compound of theinvention. The patient may be a human or other mammal such as otherprimates. Treatment of humans, domesticated companion animals (pet) orlivestock animals suffering from certain with an effective amount of acompound of the invention is encompassed by the invention.

[0058] Additionally this invention relates to the use of the CRF1compounds of the invention as probes for the localization of receptorsin tissue sections.

[0059] The compounds of the present invention are useful for thetreatment of CNS disorders particularly affective disorders, anxietydisorders, stress-related disorders, eating disorders and substanceabuse. Affective disorders include all types of depression, bipolardisorder, cyclothymia, and dysthymia. Anxiety disorders includegeneralized anxiety disorder, panic, phobias and obsessive-compulsivedisorder. Stress-related disorders include post-traumatic stressdisorder, hemorrhagic stress, stress-induced psychotic episodes,psychosocial dwarfism, stress headaches, stress-induced immune systemsdisorders such as stress-induced fever, and stress-related sleepdisorders. Eating disorders include anorexia nervosa, bulimia nervosa,and obesity. These conditions are herein after referred to as theprimary CRF-related CNS disorders.

[0060] Arylpyrazine compounds of the invention (which includes compoundsof the Formulae I, IA, and IB, as well as below-specified Formulae Iathrough Ie, II, IIa through IIi, III, IIIa through IIIe and IV,) arealso useful in the treatment of a variety of neurological disordersincluding supranuclear palsy, AIDS related dementias, multiinfarctdementia, neurodegenerative disorders such as Alzheimer's disease,Parkinson's disease, and Huntington's disease, head trauma, spinal cordtrauma, ischemic neuronal damage, amyotrophic lateral sclerosis,disorders of pain perception such as fibromyalgia and epilepsy. Theseconditions are hereinafter referred to as the secondary CRF-related CNSdisorders.

[0061] Arylpyrazine compounds of the invention are useful as modulatorsof the G-protein coupled receptor function.

[0062] Additionally, arylpyrazine compounds of the invention are usefulas modulators of the CRF receptor in the treatment of a number ofgastrointestestinal, cardiovascular, hormonal, autoimmune andinflammatory conditions. Such conditions include irritable bowelsyndrome, ulcers, Crohn's disease, spastic colon, diarrhea, postoperative ilius and colonic hypersensitivity associated withpsychopathological disturbances or stress, hypertension, tachycardia,congestive heart failure, infertility, euthyroid sick syndrome,inflammatory conditions effected by rheumatoid arthritis andosteoarthritis, pain, asthma, psoriasis and allergies. These conditionsare referred to hereinafter as the non-CNS CRF-related disorders.

[0063] Arylpyrazine compounds of the invention are also useful asmodulators of the CRF, receptor in the treatment of animal conditionsassociated with aberrant CRF levels. These conditions include porcinestress syndrome, bovine shipping fever, equine paroxysmal fibrillation,and dysfunctions induced by confinement in chickens, sheering stress insheep or human-animal interaction related stress in dogs, psychosocialdwarfism and hypoglycemia. These animal conditions are referred tohereinafter as the CRF-related animal disorders.

[0064] According to yet another aspect, the present invention providespharmaceutical compositions comprising one or more aryl pyrazinecompound of the invention of a pharmaceutically acceptable salt thereof,particularly for use in the treatment of any of the primary CNSdisorders, secondary CNS disorders, non-CNS CRF-related disorders, orCRF-related animal disorders.

[0065] According to a still further aspect of the invention,arylpyrazine compounds of the invention (and especially labeledcompounds of this invention) are useful as standards and reagents indetermining the ability of a potential pharmaceutical to bind to the CRFreceptor. Other aspects of the invention are disclosed infra.

DETAILED DESCRIPTION OF THE INVENTION

[0066] The invention provides compounds of Formula I shown above.Preferred compound of the invention include those of the followingFormula Ia:

[0067] or a pharmaceutically acceptable salt thereof, wherein:

[0068] R₁ is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,halogen, CN, C₁₋₄ haloalkyl, trifluoromethyl, trifluoromethoxy, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), and S(O),(C₁₋₄alkyl);

[0069] R₂ is selected from the group consisting of —XR_(A) and Y,wherein —X, R_(A), and Y are defined below; and

[0070] R₃ is selected from the group consisting of hydrogen, halogen,C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₄ alkyl)(C₁₋₄ alkyl),and —S(O)n(C₁₋₄ alkyl), haloalkyl, trifluoromethyl, trifluoromethoxy,—XR_(A) and Y;

[0071] R₄ is absent or an oxygen atom;

[0072] Ar is phenyl, mono-, di-, or tri-substituted with R_(C), or

[0073] Ar is selected from the group consisting of:

[0074] naphthyl, pyridyl, pyridonyl, pyrimidinyl, and thiophenyl, eachof which is unsubstituted or mono-, di-, or tri-substituted with R_(C);

[0075] with the proviso that if Ar is phenyl substituted with halogen,napthyl, or naphthyl substituted with halogen, then the compounds whereR₃ is hydrogen are excluded;

[0076] R_(A) and R_(B), which may be the same or different, areindependently selected at each occurrence from the group consisting ofhydrogen and straight, branched, or cyclic alkyl groups consisting of 1to 8 carbon atoms, which may contain one or more double or triple bonds,each of which may be further substituted with one or more substituent(s)selected from oxo, hydroxy, halogen, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)(C₁₋₄ alkyl), NHC(O)(C₁₋₄alkyl), —N(C₁₋₄ alkyl)C(═O)(C₁₋₄alkyl), —NHS(O)_(n)(C₁₋₄ alkyl), —S(O)_(n)(C₁₋₄ alkyl), —S(O)_(n)NH(C₁₋₄alkyl), —S(O)_(n)N(C₁₋₄ alkyl)(C₁₋₄ alkyl), and Z;

[0077] R_(C) is independently selected at each occurrence from the groupconsisting of halogen, cyano, haloalkyl, trifluoromethyl,trifluoromethoxy, hydroxy, amino, and C₁₋₄ alkyl optionally substitutedwith 0-2 R_(D), C₂₋₆ alkenyl substituted with 0-2 R_(D), C₁₋₄alkynylsubstituted with 0-2 R_(D), C₃₋₇ cycloalkyl substituted with 0-2 R_(D),(C₃₋₇cycloalkyl)C₁₋₄ alkyl substituted with 0-2 R_(D), —O(C₁₋₄ alkyl)substituted with 0-2 R_(D), —NH(C₁₋₄alkyl) substituted with 0-2 R_(D),—N(C₁₋₄alkyl)(C₁₋₄ alkyl) each independently substituted with 0-2 R_(D),—XR_(A), and Y;

[0078] R_(D) is independently selected at each occurrence the groupconsisting of halogen, hydroxy, cyano, C1₋₄alkyl-O(C₁₋₄alkyl),—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl), (C₁₋₄alkyl), morpholino, pyrrolidino,piperidino, thiomorpholino, piperazino, 4-hydroxypiperidino, —S(O)_(n)(C₁₋₄alkyl), trifluoromethyl, trifluoromethoxy, CO(C₁₋₄alkyl),CONH(C₁₋₄alkyl), CON(C₁₋₄alkyl)(C₁₋₄alkyl), —XR_(A), and Y;

[0079] X is independently selected at each occurrence from the groupconsisting of —CH₂—, —CHR_(B)—, —O—, C(═O)—, —C(═O)O—, —S(O)_(n), —NH—,—NR_(B)—, —C(═O)NH—, —C(═O)NR_(B)—, —S(O)_(n)NH—, —S(O)_(n)NR_(B)—,—OC(═S)S—, —NHC(═O)—, —NR_(B)C(═O)—, —NHS(O)_(n)-,—OSiH_(n)(C₁₋₄alkyl)_(2-n), and —NR_(B)S(O)_(n)-; and

[0080] Y and Z are independently selected at each occurrence from thegroup consisting of: 3- to 7-membered carbocyclic and heterocyclicgroups, which are saturated, unsaturated, or aromatic, which may besubstituted with one or more substituents selected from halogen,haloalkyl, oxo, hydroxy, amino, C₁₋₄ alkyl, —O(C₁₋₄ alkyl),—NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)(C₁₋₄alkyl), and —S(O)_(n)(C₁₋₄ alkyl),and said 3- to 7-membered heterocyclic groups contain one or moreheteroatom(s) selected from N, O, and S, with the point of attachmentbeing either carbon or nitrogen; and

[0081] n is independently selected at each occurrence from 0, 1, and 2.

[0082] Preferred compounds of general Formula Ia are those where:

[0083] R₄ is absent and Ar is phenyl, mono-, di-, or tri-substitutedwith R_(C), and R₁ and R₃ are independently selected from the groupconsisting of hydrogen, halogen, methyl, ethyl, ethoxy and methoxy.

[0084] Such compounds are referred to herein as compounds of generalFormula lb.

[0085] More preferred compounds of the invention are those of generalFormula Ia where:

[0086] R₄ is absent and Ar is phenyl, mono-, di-, or tri-substitutedwith R_(C); and R_(A) and R_(B), which may be the same or different, areindependently straight, branched, or cyclic alkyl groups having from 1to 8 carbon atoms, which may contain one or more double or triple bonds.

[0087] Such compounds are referred to as compounds of Formula Ic.

[0088] Particularly preferred are compounds of general Formula Ia arethose where:

[0089] R₄ is absent and Ar is phenyl mono-, di-, or tri-substituted withR_(C); R_(A) and R_(B), which may be the same or different, areindependently selected at each occurrence from the group consisting of:straight, branched, and cyclic alkyl groups having from 1 to 8 carbonatoms, which may contain one or more double or triple bonds; and

[0090] R₁ and R₃ are independently selected from the group consisting ofhydrogen, halogen, methyl, ethyl, ethoxy, and methoxy.

[0091] Such compounds are referred to herein as compounds of generalFormula Id.

[0092] Particularly preferred are compounds of general Formula Ia arethose where:

[0093] wherein A is NR_(A) or O.

[0094] Such compounds are referred to herein as compounds of generalFormula Ie.

[0095] Even more preferred compounds of the invention are those ofgeneral Formula II:

[0096] Formula II

[0097] wherein

[0098] R_(X) and R_(Y) are the same or different and are independentlyselected straight, branched, or cyclic alkyl groups having from 1 to 8carbon atoms, which may contain one or more double or triple bonds, eachof which may be further substituted with one or more substituent(s)independently selected from hydroxy, halogen, —O(C₁₋₄ alkyl), —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), and optionally substituted phenyl.

[0099] Other preferred compounds of the invention include those ofgeneral Formula II (above) and pharmaceutically acceptable saltsthereof, wherein:

[0100] Ar is phenyl, mono-, di-, or tri-substituted with R_(C); and R₁and R₃ are independently selected from the group consisting of hydrogen,halogen, methyl, ethyl, ethoxy and methoxy.

[0101] Such compounds are referred to herein as compounds of generalFormula Ia.

[0102] Other preferred compounds of the invention include those ofgeneral Formula II (above) and pharmaceutically acceptable saltsthereof, wherein:

[0103] R₁ and R₃ are independently chosen from halogen, C₁₋₄ alkyl,—O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl,trifluoromethyl, and trifluoromethoxy; and

[0104] Ar is phenyl, which is mono-, di-, or trisubstituted with one ormore substituent(s) independently selected from:

[0105] halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy,hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy),mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.

[0106] Such compounds are referred to herein as compounds of generalFormula IIb.

[0107] Other preferred compounds of the invention include those ofgeneral Formula II (above) and pharmaceutically acceptable saltsthereof, wherein:

[0108] R_(X) is hydrogen;

[0109] R_(Y) is chosen from the group consisting of:

[0110] straight, branched, or cyclic alkyl groups having from 1 to 8carbon atoms, which may contain one or more double or triple bonds;

[0111] R₁ and R₃ are independently chosen from halogen, C₁₋₄ alkyl,—O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl,trifluoromethyl, and trifluoromethoxy; and

[0112] Ar is phenyl, which is mono-, di-, or trisubstituted withsubstituent(s) independently selected from:

[0113] halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy,hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy),mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.

[0114] Such compounds are referred to herein as compounds of generalFormula IIc.

[0115] Other preferred compounds of the invention include those ofgeneral Formula II (above) and pharmaceutically acceptable saltsthereof, wherein:

[0116] R_(X) is hydrogen;

[0117] R_(Y) is chosen from the group consisting of:

[0118] straight, branched, or cyclic alkyl groups having from 1 to 8carbon atoms, which may contain one or more double or triple bonds;

[0119] R₁ and R₃ are independently chosen from halogen, C₁₋₄ alkyl,—O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl,trifluoromethyl, and trifluoromethoxy; and

[0120] Ar is a phenyl group of the formula:

[0121] wherein L indicates a bond to the pyrazine ring in Formula A;

[0122] and the phenyl group is substituted at one, two or three ofpositions 2, 4, and 6 with substituent(s) independently selected from:

[0123] halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy,hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy),mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.

[0124] Such compounds are referred to herein as compounds of generalFormula IId.

[0125] Other preferred compounds of the invention include those ofgeneral Formula II (above) and pharmaceutically acceptable saltsthereof, wherein:

[0126] R_(X) is hydrogen;

[0127] R_(Y) is chosen from the group consisting of:

[0128] straight, branched, or cyclic alkyl groups having from 1 to 8carbon atoms, which may contain one or more double or triple bonds;

[0129] R₁ and R₃ are independently chosen from halogen, C₁₋₄ alkyl—O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl,trifluoromethyl, and trifluoromethoxy; and

[0130] Ar is a phenyl group of the formula:

[0131] wherein L indicates a bond to the pyrazine ring in Formula A;

[0132] and the phenyl group is substituted at positions 2 and 4 withsubstituents independently selected from:

[0133] halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy,hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy),mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.

[0134] Such compounds are referred to herein as compounds of generalFormula IIe.

[0135] Other preferred compounds of the invention include those ofgeneral Formula II (above) and pharmaceutically acceptable saltsthereof, wherein:

[0136] wherein:

[0137] R₁ and R₃ are independently chosen at each occurrence fromhalogen, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)(C₁₋₄ alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy;and

[0138] Ar is a phenyl group of the formula:

[0139] wherein L indicates a bond to the pyrazine ring in Formula A;

[0140] and the phenyl group is substituted at one, two or three ofpositions 2, 4, and 6 with substituent(s) independently selected from:

[0141] halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy,hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy),mono- or di(C₁₋₄) amino (C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.

[0142] Such compounds are referred to herein as compounds of generalFormula IIf.

[0143] Other preferred compounds of the invention include those ofgeneral Formula II (above) and pharmaceutically acceptable saltsthereof, wherein:

[0144] wherein

[0145] R is independently selected at each occurrence from the groupconsisting of: hydrogen, halogen, cyano, haloalkyl, trifluoromethyl,trifluoromethoxy, hydroxy, amino, Cl ₆alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy(C₁₋₄alkoxy), mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- ordi(C₁₋₄alkyl)amino; and

[0146] R₁ and R₃ are independently chosen from halogen, C₁₋₄ alkyl,—O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl,trifluoromethyl, and trifluoromethoxy.

[0147] Such compounds are referred to herein as compounds of generalFormula IIg.

[0148] Other preferred compounds of the invention include those ofgeneral Formula II (above) and pharmaceutically acceptable saltsthereof, wherein:

[0149] Ar is phenyl, which is mono-, di-, or tri-substituted with R_(C);

[0150] R_(X) and R_(Y), which may be the same or different, areindependently selected at each occurrence from the group consisting of:straight, branched, and cyclic alkyl groups having from 1 to 8 carbonatoms, which may contain one or more double or triple bonds; and

[0151] R₁ and R₃ are independently selected from the group consisting ofhydrogen, halogen, methyl, ethyl, ethoxy, and methoxy.

[0152] Such compounds are referred to herein as compounds of generalFormula IIh.

[0153] Other preferred compounds of the invention include those ofgeneral Formula II (above) and pharmaceutically acceptable saltsthereof, wherein:

[0154] wherein R_(X) and R are independently hydrogen or C₁₋₈ alkyl; orNR_(X)R_(Y) is:

[0155] wherein z is 0 or 1.

[0156] Such compounds are referred to herein as compounds of generalFormula IIi.

[0157] Other highly preferred compounds are those of general FormulaIII:

[0158] wherein:

[0159] R_(X) is chosen from the group consisting of:

[0160] straight, branched, or cyclic alkyl groups, including(cycloalkyl)alkyl groups, having from 1 to 8 carbon atoms, which maycontain one or more double or triple bonds, each of which may be furthersubstituted with one or more substituent(s) independently selected from

[0161] (a) hydroxy, halogen, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)(C₁₋₄ alkyl), and

[0162] (b) 3- to 7-membered carbocyclic and heterocyclic groups, whichare saturated, unsaturated, or aromatic, which may be substituted withone or more substituents selected from halogen, haloalkyl, oxo, hydroxy,amino, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), and —N(C₁₋₄alkyl)(C₁₋₄ alkyl)and wherein said 3- to 7-membered heterocyclic groupscontain one or more heteroatom(s) selected from N, O, and S, with thepoint of attachment being either carbon or nitrogen.

[0163] Other preferred compounds of the invention include those ofgeneral Formula III (above) and pharmaceutically acceptable saltsthereof, wherein:

[0164] R₁ is selected from straight, branched, or cyclic alkyl groupscontaining of 1 to 8 carbon atoms, which may contain one or more doubleor triple bonds; and;

[0165] R₁ and R₃ are independently chosen from halogen, C₁₋₄ alkyl,—O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl,trifluoromethyl, and trifluoromethoxy; and

[0166] Ar is phenyl, which is mono-, di-, or trisubstituted with one ormore substituent(s) independently selected from:

[0167] halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy,hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy),mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.

[0168] Such compounds are referred to herein as compounds of generalFormula IIa.

[0169] Other preferred compounds of the invention include those ofgeneral Formula III (above) and pharmaceutically acceptable saltsthereof, wherein:

[0170] Ar is a phenyl group of the formula:

[0171] wherein L indicates a bond to the pyrazine ring in Formula III;

[0172] and the phenyl group is substituted at one, two, or three ofpositions 2, 4, and 6 with substituent(s)independently selected from:

[0173] halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy,hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy),mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.

[0174] Such compounds are referred to herein as compounds of generalFormula IIIb.

[0175] Other preferred compounds of the invention include those ofgeneral Formula III (above) and pharmaceutically acceptable saltsthereof, wherein:

[0176] Ar is a phenyl group of the formula:

[0177] wherein L indicates a bond to the pyrazine ring in Formula III;

[0178] and the phenyl group is substituted at positions 2 and 4 withsubstitutuents independently selected from halogen, cyano, haloalkyl,trifluoromethyl, trifluoromethoxy, hydroxy, amino, C₁₋₆ alkyl,C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy), mono- or di(C₁₋₄)amino(C₁₋₄alkoxy),and mono- or di(C₁₋₄ alkyl)amino.

[0179] Such compounds are referred to herein as compounds of generalFormula IIIc.

[0180] Other preferred compounds of the invention include those ofgeneral Formula III (above) and pharmaceutically acceptable saltsthereof, wherein:

[0181] R₁ and R₃ are independently chosen from halogen, C₁₋₄ alkyl,—O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), halo alkyl,trifluoromethyl, and trifluoromethoxy; and

[0182] Ar is a phenyl group of the formula:

[0183] wherein L indicates a bond to the pyrazine ring in Formula B; andthe phenyl group is substituted at one, two, or three of positions 2, 4,and 6 with substituent(s)independently selected from: halogen, cyano,haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C₁₋₆alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy), mono- ordi(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.

[0184] Such compounds are referred to herein as compounds of generalFormula IIId.

[0185] Other preferred compounds of the invention include those ofgeneral Formula III (above) and pharmaceutically acceptable saltsthereof, wherein:

[0186] R₁ and R₃ are independently selected from the group consisting ofhydrogen, halogen, methyl, ethyl, ethoxy and methoxy.

[0187] Such compounds are referred to herein as compounds of generalFormula IIIe.

[0188] Another preferred compound of the invention include2-(2-methoxy-5-triflurormethoxyphenyl)-3-ethyl-6-methylamino-5-(1-ethylpropoxy)-pyrazine.and pharmaceutically acceptable salts thereof, the compound structureis:

DEFINITIONS

[0189] The compounds herein described may have one or more asymmetriccenters or planes. Compounds of the present invention containing anasymmetrically substituted atom may be isolated in optically active orracemic forms. It is well known in the art how to prepare opticallyactive forms, such as by resolution of racemic forms (racemates), byasymmetric synthesis, or by synthesis from optically active startingmaterials. Resolution of the racemates can be accomplished, for example,by conventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiral HPLCcolumn. Many geometric isomers of olefins, C═N double bonds, and thelike can also be present in the compounds described herein, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral (enantiomeric and diastereomeric), andracemic forms, as well as all geometric isomeric forms of a structureare intended, unless the specific stereochemistry or isomeric form isspecifically indicated.

[0190] The CRF antagonist compounds provided by this invention andlabeled derivatives thereof are also useful as standards and reagents indetermining the ability of a potential pharmaceutical to bind to the CRFreceptor.

[0191] Labeled derivatives the CRF antagonist compounds provided by thisinvention are also useful as radiotracers for positron emissiontomography (PET) imaging or for single photon emission computerizedtomography (SPECT).

[0192] The term “substituted,” as used herein, means that any one ormore hydrogens on the designated atom is replaced with a selection fromthe indicated group, provided that the designated atom's normal valenceis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., =0), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. Thepresent invention is intended to include all isotopes of atoms occurringin the present compounds. Isotopes include those atoms having the sameatomic number but different mass numbers, By way of general example andwithout limitation, isotopes of hydrogen include tritium and deuterium.Isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

[0193] When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-2 R*, then said group mayoptionally be substituted with up to two R* groups and R* at eachoccurrence is selected independently from the definition of R*. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

[0194] As indicated above, various substituents of the various formulaeare “optionally substituted”, including Ar, R₁, R₂, and R₃ of Formula I,and such substituents as recited in the sub-formulae such as Formulae Iaand the like. When substituted, those substituents (Ar, R₁, R₂, and R₃)may be substituted by other than hydrogen at one or more availablepositions, typically I to 3 or 4 positions, by one or more suitablegroups such as those disclosed herein. Suitable groups that may bepresent on a “substituted” Ar, R₁, R₂, and R₃ group or other substituentinclude e.g. halogen such as fluoro, chloro, bromo and iodo; cyano;hydroxyl; nitro; azido; alkanoyl such as a C₁₋₆ alkanoyl group such asacyl and the like; carboxamido; alkyl groups including those groupshaving 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms;alkenyl and alkynyl groups including groups having one or moreunsaturated linkages and from 2 to about 12 carbon, or 2, 3, 4, 5 or 6carbon atoms; alkoxy groups having those having one or more oxygenlinkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6carbon atoms; aryloxy such as phenoxy; alkylthio groups including thosemoieties having one or more thioether linkages and from 1 to about 12carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms; alkylsulfinyl groupsincluding those moieties having one or more sulfinyl linkages and from 1to about 12 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms;alkylsulfonyl groups including those moieties having one or moresulfonyl linkages and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5,or 6 carbon atoms; aminoalkyl groups such as groups having one or more Natoms and from 1 to about 12 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbonatoms; carbocyclic aryl having 6 or more carbons, particularly phenyl(e.g. an Ar group being a substituted or unsubstituted biphenyl moiety);aralkyl having 1 to 3 separate or fused rings and from 6 to about 18carbon ring atoms, with benzyl being a preferred group; aralkoxy having1 to 3 separate or fused rings and from 6 to about 18 carbon ring atoms,with O-benzyl being a preferred group; or a heteroaromatic orheteroalicyclic group having 1 to 3 separate or fused rings with 3 toabout 8 members per ring and one or more N, O or S atoms, e.g.coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl,benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl,morpholino and pyrrolidinyl.

[0195] As used herein, the substitution position of a substituent on aphenyl ring is dependent on the point of attachment of the substitutentto the phenyl ring relative to the point of attachment of the phenylgroup to the remainder of the chemical compound. For example, Lindicates the point of attachment of the phenyl ring to the remainder ofthe chemical compound. The numbers 2, 3, 4, 5 and 6 identify theindividual ring atoms to which substituents can be attached.

[0196] As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, having thespecified number of carbon atoms. Examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, and s-pentyl. Alkyl groups typically have 1 to about16 carbon atoms, more typically 1 to about 12 carbon atoms. Preferredalkyl groups are C₁-C₆ alkyl groups. Especially preferred alkyl groupsare methyl, ethyl, propyl, butyl, 3-pentyl.

[0197] As used herein, “cycloalkyl” is intended to include saturatedring groups, having the specified number of carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Cycloalkyl groupstypically will have 3 to about 8 ring members.

[0198] In the term “(C₃₋₆ cycloalkyl)C₁₋₄ alkyl”, as defined above, thepoint of attachment is on the alkyl group. This term encompasses, but isnot limited to, cyclopropylmethyl, cyclohexylmethyl, cyclohexylmethyl.

[0199] As used here, “alkenyl” is intended to include hydrocarbon chainsof either a straight or branched configuration and one or moreunsaturated carbon-carbon bonds which may occur in any stable pointalong the chain, such as ethenyl and propenyl. Alkenyl groups typicallywill have 2 to about 12 carbon atoms, more typically 2 to about 12carbon atoms.

[0200] As used herein, “alkynyl” is intended to include hydrocarbonchains of either a straight or branched configuration and one or moretriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl and propynyl. Alkynyl groups typically will have2 to about 16 carbon atoms, more typically 2 to about 12 carbon atoms.

[0201] As used herein, “haloalkyl” is intended to include both branchedand straight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. Typicalhaloalkyl groups will have 1 to about 16 carbon atoms, more typically 1to about 12 carbon atoms.

[0202] As used herein, “alkoxy” represents an alkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy,n-pentoxy, 2-pentoxy, 3- pentoxy, isopentoxy, neopentoxy, n-hexoxy,2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Alkoxy groups typically have 1to about 16 carbon atoms, more typically 1 to about 12 carbon atoms.

[0203] As used herein, the term “alkylthio” includes those groups havingone or more thioether linkages and suitably from 1 to about 16 carbonatoms, more typically 1 to about 12 carbon atoms, still more typically 1to about 6 or 8 carbon atoms.

[0204] As used herein, the term “alkylsulfinyl” includes those groupshaving one or more sulfoxide (SO) linkage groups and suitably from 1 toabout 16 carbon atoms, more typically 1 to about 12 carbon atoms, stillmore typically 1 to about 6 or 8 carbon atoms.

[0205] As used herein, the term “alkylsulfonyl” includes those groupshaving one or more sulfonyl (SO₂) linkage groups and suitably from 1 toabout 16 carbon atoms, more typically 1 to about 12 carbon atoms, stillmore typically 1 to about 6 or 8 carbon atoms.

[0206] As used herein, the term “alkylamino” includes those groupshaving one or more primary, secondary and/or tertiary amine groups andsuitably from 1 to about 16 carbon atoms, more typically 1 to about 12carbon atoms, still more typically 1 to about 6 or 8 carbon atoms.

[0207] As used herein, “halo” or “halogen” as used herein refers tofluoro, chloro, bromo, and iodo; and “counter-ion” is used to representa small, negatively charged species such as chloride, bromide,hydroxide, acetate, sulfate, and the like.

[0208] As used herein, “carbocycle” or “carbocyclic residue” is intendedto mean any stable 3- to 7-membered monocyclic or bicyclic or 7-to13-membered bicyclic or tricyclic, any of which may be saturated,partially unsaturated, or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

[0209] As used herein, the term “heterocycle” or “heterocycloalkyl” isintended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to10-membered bicyclic heterocyclic ring which is saturated partiallyunsaturated or unsaturated (aromatic), and which consists of carbonatoms and from 1 to 4 heteroatoms independently selected from the groupconsisting of N, O and S and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quarternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1. Asused herein, the term “aromatic heterocyclic system” or similar termsuch as “heteroaryl” is intended to mean a stable 5-to 7-memberedmonocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclicaromatic ring which consists of carbon atoms and from 1 to 4 heteroatomsindependently selected from the group consisting of N, O and S. It ispreferred that the total number of S and O atoms in the aromaticheterocycle. is not more than 1. Examples of heterocycles include, butare not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5oxadiazolyl, is1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0210] Preferred heterocycles include, but are not limited to,pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl,imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl,benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, andisatinoyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

[0211] As used herein, the term “carbocyclic aryl” includes groups thatcontain 1 to 3 separate or fused rings and from 6 to about 18 ringatoms, without hetero atoms as ring members.

[0212] Specifically preferred carbocyclic aryl groups include phenyl,and naphthyl including 1-napthyl and 2-naphthyl.

[0213] The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio. As usedherein, “pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, malefic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)-COOH where n is 0-4, and the like. The pharmaceuticallyacceptable salts of the present invention can be synthesized from theparent compound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington 's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., p. 1418 (1985), thedisclosure of which is hereby incorporated by reference.

[0214] “Prodrugs” are intended to include any covalently bonded carrierswhich release the active parent drug according to formula I in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula I are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula I wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula I is administered to a mammalian subject, cleavesto form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of formula I, and the like.

[0215] Combinations of substituents and/or variables are permissibleonly if such combinations result in stable compounds. A stable compoundor stable structure is meant to imply a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into an effective therapeutic agent. The term“therapeutically effective amount” of a compound of this invention meansan amount effective to antagonize abnormal level of CRF or treat thesymptoms of affective disorder, anxiety or depression in a host.

[0216] The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

[0217] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

[0218] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0219] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0220] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide palatableoral preparations. These compositions may be preserved by the additionof an anti-oxidant such as ascorbic acid.

[0221] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0222] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

[0223] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also besterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0224] The compounds of general Formula I may also be administered inthe form of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0225] Compounds of general Formula I may be administered parenterallyin a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

[0226] Typical subjects to which compounds of the invention may beadministered will be mammals, particularly primates, especially humans.For veterinary applications, a wide variety of subjects will besuitable, e.g. livestock such as cattle, sheep, goats, cows, swine andthe like; poultry such as chickens, ducks, geese, turkeys, and the like;and domesticated animals particularly pets such as dogs and cats. Fordiagnostic or research applications, a wide variety of mammals will besuitable subjects including rodents (e.g. mice, rats, hamsters),rabbits, primates, and swine such as inbred pigs and the like.Additionally, for in vitro applications, such as in vitro diagnostic andresearch applications, body fluids and cell samples of the abovesubjects will be suitable for use such as mammalian, particularlyprimate such as human, blood, urine or tissue samples, or blood urine ortissue samples of the animals mentioned for veterinary applications.

[0227] Dosage levels of the order of from about 0.1 mg to about 140 mgof a compound of the invention per kilogram of body weight per day areuseful in the treatment of the above-indicated conditions (about 0.5 mgto about 7 g per patient per day). The amount of active ingredient thatmay be combined with the carrier materials to produce a single dosageform will vary depending upon the host treated and the particular modeof administration. Dosage unit forms will generally contain between fromabout 1 mg to about 500 mg of an active ingredient.

[0228] Frequency of dosage may also vary depending on the compound usedand the particular disease treated. However, for treatment of most CNSdisorders, a dosage regimen of 4 times daily or less is preferred. Forthe treatment of stress and depression a dosage regimen of 1 or 2 timesdaily is particularly preferred.

[0229] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

[0230] Preferred compounds of the invention will have certainpharmacological properties. Such properties include, but are not limitedto oral bioavailability, low toxicity, low serum protein binding anddesirable in vitro and in vivo half-lifes. Penetration of the bloodbrain barrier for compounds used to treat CNS disorders is necessary,while low brain levels of compounds used to treat periphereal disordersare often preferred.

[0231] Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

[0232] Serum protein binding may be predicted from albumin bindingassays. Such assays are described in a review by Oravcová, et al.(Journal of Chromatography B (1996) volume 677, pages 1-27).

[0233] Compound half-life is inversely proportional to the frequency ofdosage of a compound. In vitro half-lives of compounds may be predictedfrom assays of microsomal half-life as described by Kuhnz and Gieschen(Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).Alternatively, compound half-life may be predicted from an in vitromicrosomal assay such as the assay given in example 99b.

[0234] The present invention also pertains to methods for altering theactivity of CRF receptors, said method comprising exposing cellsexpressing such receptors to an effective amount of a compound of theinvention, wherein the compound is present in the solution at aconcentration sufficient to specifically alter the signal transductionactivity in response to CRF in cells expressing high levels of CRF 1receptors in vitro. This method includes altering the signaltransduction activity of CRF receptors in vivo, e.g., in a patient givenan amount of a compound of Formula I that would be sufficient to alterthe signal transduction activity in response to CRF in cells expressinghigh levels of CRF1 in vitro. The amount of a compound that would besufficient to alter the signal transduction activity in response to CRFreceptors may be determined via an assay of CRF receptor mediated signaltransduction, such as an assay wherein the binding of CRF to a cellsurface CRF receptor effects a changes in reporter gene expression.

[0235] The present invention also pertains to packaged pharmaceuticalcompositions for treating disorders responsive to C5a receptormodulation, e.g., eating disorders, depression or stress. The packagedpharmaceutical compositions include a container holding atherapeutically effective amount of at least one CRF1 receptor modulatoras described supra and instructions for using the treating disorderresponsive to CRF1 receptor modulation in the patient.

PREPARATION OF ARYLPYRAZINES

[0236] The compounds of the present invention can be prepared in anumber of ways well known to one skilled in the art of organicsynthesis. The compounds of the present invention can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Each of the referencescited below are hereby incorporated herein by reference. Preferredmethods for the preparation of compounds of the present inventioninclude, but are not limited to, those described in Scheme I, Scheme II,and Scheme III. Those who are skilled in the art will recognize that thestarting materials may be varied and additional steps employed toproduce compounds encompassed by the present invention. All referencescited herein are hereby incorporated in their entirety herein byreference. The following abbreviations are used herein: AcOH acetic acidDMF N,N-dimethylformamide Et₂O diethyl ether EtOAc ethyl acetate EtOHethanol NaH sodium hydride NaHMDS sodium bis(trimethylsilyl)amide THFtetrahydrofuran EX# example number

[0237]

[0238] According to the general method A, wherein R₁ and R₃ are asdefined for formula I and Hal represents a halogen atom, suitablychloride or bromide, the halide in VI can be displaced by an amine or(thio)alkoxide nucleophile. Thus, aminopyrazine can be prepared from VIand an amine in the presence of a suitable transition metal catalystsuch as but not limited to palladium(II) acetate ortris(dibenzylideneacetone)dipalladium(0), a ligand such as but notlimited to 1,1′-bis(diphenylphosphine)ferrocene,2,2′-bis(diphenylphosphine)-1,1′-binaphthyl,dicyclohexyl(2-biphenyl)phosphine, tricyclohexylphosphine, ortri-tert-butylphosphine, and a base such as sodium or potassiumtert-butoxide in inert solvents such as but not limited to toluene,ethyleneglycol dimethyl ether, diglyme, DMF, or N-methylpyrrolidinone attemperatures ranging from ambient to 100° C. (Thio)alkoxypyrazines canbe prepared by treating VI with a sodium or potassium salt of an alcoholor thiol in an inert solvent such as THF, DMF, N-methylpyrrolidinone, ormethyl sulfoxide at ambient temperature or at elevated temperature up tothe boiling point of the solvent employed. Halogenation may beaccomplished by a variety of methods known in the art, includingtreatment with N-chlorosuccinimide, bromine, N-bromosuccinimide,pyridinium tribromide, triphenylphosphine dibromide, iodine, andN-iodosuccinimide in solvents such as but not limited todichloromethane, acetic acid, or methyl sulfoxide. The bromopyrazine canbe converted to arylpyrazine VII by a transition metal-catalyzedcoupling reaction with a metalloaryl reagent (Ar-[M]). More commonlyemployed reagent/catalyst pairs include aryl boronic acid/palladium(0)(Suzuki reaction; N. Miyaura and A. Suzuki, Chemical Review 1995, 95,2457), aryl trialkylstannane/palladium(0) (Stille reaction; T. N.Mitchell, Synthesis 1992, 803), arylzinc/palladium(0) and arylGrignard/nickel(II). Palladium(0) represents a catalytic system made ofa various combination of metal/ligand pair which includes, but notlimited to, tetrakis(triphenylphosphine)palladium(0), palladium(II)acetate/tri(o-tolyl)phosphine,tris(dibenzylideneacetone)dipalladium(0)/tri-tert-butylphosphine anddichloro[1,1′-bis(diphenylphosphine)ferrocene]palladium(0). Nickel(II)represents a nickel-containing catalyst such as[1,2-bis(diphenylphosphino)ethane]dichloronickel(II) and[1,3-bis(diphenylphosphino)propane]dichloronickel(II). The arylpyrazineVII, when X is NH, may be further transformed to VIII by N-alkylation.The N—H group is deprotonated by a strong base such as but not limitedto alkali metal hydride, alkali metal amide, or alkali metal alkoxide ininert solvents such as but not limited to THF, DMF, or methyl sulfoxide.Alkylation may be conducted using alkyl halide, suitably bromide oriodide, at temperatures ranging from 0° C. to

[0239] In an alternative way, compounds of Formula VII can be preparedas outlined in Scheme II. Transition metal-catalyzed coupling of thehalo pyrazine VI as described in the Method A can provide theintermediate VIII. Oxidation of sterically less hindered nitrogen can beeffected by using a variety of oxidizing agents known in the art, whichincludes m-chloroperoxybenzoic acid, trifluoroperacetic acid, hydrogenperoxide, and monoperoxyphthalic acid. The N-oxide can undergorearrangement to give chloropyrazine IX upon the action of phosphorusoxychloride at temperatures ranging from ambient to 100° C. Displacementof the chloride with a nitrogen, sit oxygen, or sulfur nucleophile asdescribed in the Method A can furnish the compounds of Formula VII.

[0240] Yet another way of preparing compounds of formula VII isillustrated in the Scheme III.

[0241] Compounds of formula X, 3,6-dialkyl-2,5-dichloropyrazines, can beprepared from 2-alkylglycine according to a known literature procedure(Ref: Chemical and Pharmaceutical Bulletin of Japan 1979, 27, 2027).Nucleophilic displacement of one chloride followed by Suzuki-typecoupling at the other, as described in the Method A, can furnish thecompounds of formula VII.

[0242] Still another way of preparing compounds of formula VII isillustrated in Scheme IV. Commercially available 2,6-Dichloropyrazinecan undergo monosubstitution with nitrogen, oxygen, or sulfurnucleophile to give XI. Thus, X may react with an amine in solvents suchas but not limited to dichloromethane, acetonitrile, THF, DMF,N-methylpyrrolidinone, methyl sulfoxide, methanol, ethanol, andisopropanol at temperatures ranging from 0° C. to the boiling point ofthe solvent. In addition, X may react with a sodium or potassium(thio)alkoxide in inert solvents such as but not limited to THF, DMF,N-methylpyrrolidinone, or methyl sulfoxide at temperatures ranging from0° C. to ambient temperature. Resulting monochloropyrazine XI can behalogenated by using the conditions described in the Method A to give amixture of regioisomeric bromides XIIa and XIIb. Transitionmetal-catalyzed (hetero)aryl-aryl coupling of XIIa, as described in theMethod A, followed by another halogenation can provide VII (R₁=Hal,R₃═Cl) which can be further converted to VII by displacing one or bothof the halgen atoms, either sequentially or simultaneously, with avariety of nucleophiles (R₁-[M] and R₃-[M]), same or different, in thepresence or absence of a transition metal catalyst. The aforementionednucleophiles may include sodium or potassium (thio)alkoxide, alkylamine,and organometallic reagent such as but not limited to alkyl Grignardreagents, alkylboronic acids or its ester, or alkylstannanes. Theaforementioned transition metal catalyst may represent palladium ornickel catalysts described in the Method A. The other regioisomericbromide XIIb can also be converted to VII by changing the order of thetransformation sequence. Those who are skilled in the art will alsorecognize that one can further change the order of transformations toprepare the compounds of Formula VII by way of the intermediate XIII.

[0243] As discussed above, preferred arylpyrazines of the inventionexhibit good activity in standard in vitro CRF receptor binding assays,specifically the assay as specified in Example 96, which follows.References herein to “standard in vitro receptor binding assay” areintended to refer to that protocol as defined in Example 96 whichfollows. Generally preferred compounds preferred arylpyrimidines of theinvention have an IC₅₀ of about 10 micromolar or less, still morepreferably and IC₅₀ of about 100 nanomolar or less even more preferablyan IC₅₀ of about 10 nanomolar or less or even 1 nanomolar or less insuch a defined standard in vitro CRF receptor binding assay asexemplified by Example 96 which follows.

EXAMPLES

[0244] The preparation of the compounds of the present invention isillustrated further by the following examples, which are not to beconstrued as limiting the invention in scope or spirit to the specificprocedures and compounds described in them.

[0245] Commercial reagents were used without further purification. roomor ambient temperature refers to 20 to 25° C. Concentration in vacuoimplies the use of a rotary evaporator. TLC refers to thin layerchromatography. Proton nuclear magnetic resonance (¹H NMR) spectral datawere obtained at 300 or 400 MHz. Mass spectral data were obtained eitherby CI or APCI methods.

Example 1

[0246][N-([-ethyl)propyl]-5-(2,4-dimethoxyphenyl)-3,6-dimethylpyrazine-2-amine[Formula I: Ar=2,4-dimethoxyphenyl; R₂=-N-(1-ethyl)propyl; R₁═R₃═CH₃]

[0247] A. To a mixture of 2-chloro-3,6-dimethylpyrazine (0.83 mmol),tris(dibenzylideneacetone)dipalladium(0) (2 mol %), and BINAP (6 mol %)in ethyleneglycol dimethyl ether (2 mL) under nitrogen is added1-ethylpropylamine (1.0 mmol) followed by sodium tert-butoxide (1.25mmol). The mixture is stirred at 70-80° C. for 2.5 h, diluted withaqueous ammonium chloride, and extracted 1:1 hexane-Et₂O. Combinedextracts are dried (sodium sulfate), filtered, concentrated, andchromatographed on silica gel (10:1 to 4:1 hexane-EtOAc eluent) to givethe aminopyrazine.

[0248] B. A solution of N-(1-ethyl)propyl-3,6-dimethylpyrazine-2-amine(0.72 g; 3.7 mmol) in dichloromethane (20 mL) is cooled to 0° C. andN-bromosuccinimide (0.72 g; 4.1 mmol) is added in portions. After theaddition, the mixture is further stirred for 1 h while being allowed towarm to room temperature. The mixture is then concentrated to a smallvolume in vacuo, triturated with hexane, filtered, washed with hexane,and the filtrate is concentrated and chromatographed on silica gel togive the bromide (1.07 g).

[0249] C. A mixed solution of5-bromo-[N-(1-ethyl)propyl]-3,6-dimethylpyrazine-2-amine (0.40 g; 1.47mmol) and tetrakis(triphenylphosphine)palladium(0) (33 mg; 2 mol %) inethyleneglycol dimethyl ether (8 mL) is stirred at room temperature for15 min, when 2,4-dimethoxybenzeneboronic acid (1.76 mmol) and an aqueoussolution of sodium carbonate (1.0M, 4 mL) are added sequentially. Themixture is heated to 75 C with stirring for 1.5 h, then diluted with0.1N sodium hydroxide and extracted twice with 1:1 hexane-ethyl ether.Combined extracts are dried (sodium sulfate), filtered, concentrated,and chromatographed on silica (4:1 to 1:1 hexane-EtOAc) to give thetitle compound (0.50 g): lH NMR (CDCl3, 400 MHz) δ 0.95 (t, 6H), 1.6 (m,4H), 2.2 (s, 3H), 2.4 (s, 3H), 3.75 (s, 3H), 3.85 (s, 3H), 3.95 (br d,1H), 4.1 (br q, 1H), 6.5 (s, 1H), 6.55 (d, 1H) 7.2 (d, 1H); MS (CI) 330.

[0250] Examples 2-20a in the Table I may be prepared following themethods described in Example 1. TABLE I

EX# R_(A) R_(B) Ar 1H NMR (CDCl3) MS (Cl) NAME  2 H 1-ethylpropyl2,4-dichlorophenyl 1.0 (t, 6H), 1.6 (m, 4H), 2.2 (s, 3H), 3383,6-dimethyl-N-(1-ethylpropyl)-5- 2.4 (s, 3H), 4.05 (br, 2H), 7.25 (d,(2,4-dichlorophenyl)pyrazin-2- 1H), 7.3 (d, 1H), 7.45 (s, 1H) amine  3 H1-ethylpropyl 4-methoxy-2- 1.0 (t, 6H), 1.5-1.7 (m, 4H), 2.1 3263,6-dimethyl-N-(1-ethylpropyl)-5- methylphenyl (s, 3H), 2.2 (s, 3H), 2.4(s, 3H), 3.8 (2-methyl-4-methoxyphenyl) (s, 3H), 4.0 (br, 1H), 4.1 (br,1H), pyrazin-2-amine 6.75 (d, 1H), 6.8 (s, 1H), 7.1 (s, 1H)  4 H1-ethylpropyl 3-cyanophenyl 0.95 (t, 6H), 1.6 (m, 4H), 2.4 (s, 2953,6-dimethyl-N-(1-ethylpropyl)-5- 3H), 2.45 (s, 3H), 4.1 (br, 2H), 7.5(3-cyanophenyl)pyrazon-2-amine (t, 1H), 7.6 (d, 1H), 7.75 (d, 1H), 7.85(s, 1H)  5 H 1-methoxy-2- 2,4-dichlorophenyl 1.0 (t, 3H), 1.7 (m, 2H),2.2 (s, 3H), 354 3,5-dimethyl-N-(1-methoxy-2- butyl 2.4 (s, 3H), 3.4 (s,3H), 3.55 (m, butyl)-5-(2,4-dichloorophenyl) 2H), 4.25 (br, 1H), 4.55(d, 1H), 345 pyrazin-2-amine 7.25 (d, 1H), 7.3 (d, 1H), 7.45 (s, 1H)  6H 1-methoxy-2- 2,4- 1.0 (t, 3H), 1.7 (m, 2H), 2.2 (s, 3H), 3463,6-dimethyl-N-(1-methoxy-2- butyl dimethoxyphenyl 2.4 (s, 3H), 3.4 (s,3H), 3.55 (m, butyl)-5-(2,4-dimethoxyphenyl) 2H), 3.75 (s, 3H), 3.85 (s,3H), pyrazin-2-amine 4.25 (br, 1H), 4.4 (d, 1H), 6.5 (s, 1H), 6.6 (d,1H), 7.2 (d, 1H)  7 2-methoxymethyl-1- 2,4-dichlorophenyl 1.9 (m, 4H),2.2 (s, 3H), 2.6 (s, 366 2-(2,4-dichlorophenyl)-5-[2- pyrrolidine 3H),3.3 (dd, 1H), 3.35 (s, 3H), 3.4 (methoxymethyl)pyrrolidin-1- (br, 1H),3.6 (dd, 1H), 3.8 (m, 1H), yl]-3,6-dimethylpyrazine 4.6 (m, 1H), 7.3 (s,2H), 7.5 (s, 1H)  8 2-methoxymethyl-1- 2,4- 1.9 (m, 4H), 2.2 (s, 3H),2.6 (s, 358 2-(2,4-dimethoxyphenyl)-5-[2- pyrrolidine dimethoxyphenyl3H), 3.3 (dd, 1H), 3.4 (s, 2H), 3.6 (methoxymethyl)pyrrolidin-1- (dd,1H), 3.75 (s, 3H), 3.85 (s, 3H), yl]-3,6-dimethylpyrazine 4.6 (m, 1H),6.5 (s, 1H), 6.6 (d, 1H), 7.2 (d, 1H)  9 H 1-propylbutyl2,4-dichlorophenyl 1.0 (t, 6H), 1.3-1.6 (m, 8H), 2.2 3663,6-dimethyl-N-(1-propylbutyl)-5- (s, 3H), 2.35 (s, 3H), 4.0 (d, 1H),amine 4.25 (m, 1H), 7.25 (m, 2H), 7.45 (s, 1H) 10 H 1-propylbutyl4-methoxy-2- 1.0 (t, 6H), 1.3-1.6 (m, 8H), 2.1 3423,6-dimethyl-N-(1-propylbutyl)-5- methylphenyl (s, 3H), 2.2 (s, 3H),2.35 (s, 3H), (2-methyl-4-methoxyphenyl) 3.8 (s, 3H), 3.9 (d, 1H), 4.25(m, pyrazin-2-amine 1H), 6.8 (m, 2H), 7.1 (d, 1H) 11 H 1-propylbutyl4-chloro-2- 1.0 (t, 6H), 1.3-1.6 (m, 8H), 2.15 3463,6-dimethyl-N-(1-propylbutyl)-5- methylphenyl (s, 3H), 2.2 (s, 3H),2.35 (s, 3H), (2-methyl-4-chlorophenyl) pyrazin- 4.0 (d, 1H), 4.25 (br,1H), 7.1 (d, 2-amine 1H), 7.2 (d, 1H), 7.25 (s, 1H) 12 H 1-propylbutyl4-dimethylamino-2- 1.0 (t, 6H), 1.3-1.6 (m, 8H), 2.1 4093,6-dimethyl-N-(1-propylbutyl)-5- trifluoromethylphen- (s, 3H), 2.3 (s,3H), 3.0 (s, 6H), 3.9 (2-trifluoromethyl-4- yl (d, 1H), 4.25 (m, 1H),6.8 (d, 1H), dimethylaminophenyl)pyrazin-2- 7.0 (s, 1H), 7.1 (d, 1H)amine 13 H 1- 2,4-dichlorophenyl 1.0 (t, 3H), 1.9-2.1 (m, 2H), 2.2 3863,6-dimethyl-N-(3-phenylpropyl)- phenylpropyl (s, 3H), 2.4 (s, 3H), 4.6(d, 1H), 5-(2,4-dichlorophenyl)pyrazin-2- 5.15 (q, 1H), 7.2-7.4 (m, 8H)amine 14 H 1- 4-methoxy-2- 1.0 (t, 3H), 1.9-2.1 (m, 2H), 2.05 3623,6-dimethyl-N-(3-phenylpropyl)- phenylpropyl methylphenyl (s, 3H), 2.1(s, 3H), 2.4 (s, 3H), 3.8 5-(2-methyl-4-methoxyphenyl)py- (s, 3H), 4.5(d, 1H), 5.15 (q, 1H), razin-2-amine 6.8 (m, 2H), 7.0 (d, 1H), 7.2-7.4(m, 5H) 15 H 1- 4-chloo-2- 1.0 (t, 3H), 1.9-2.1 (m, 2H), 2.05 3663,6-dimethyl-N-(3-phenylpropyl)- phenylpropyl methylphenyl (s, 3H), 2.1(s, 3H), 2.4 (s, 3H), 3.8 5-(2-chloro-4-methylphenyl)pyra- (s, 3H), 4.5(d, 1H), 5.15 (q, 1H), zin-2-amine 7.0 (d, 1H), 7.2-7.4 (m, 7H) 16 H 1-4-dimethylamino-2- 1.0 (t, 3H), 1.8-2.1 (m, 2H), 2.1 4293,6-dimethyl-N-(3-phenylpropyl)- phenylpropyl trifluoromethylphen- (s,3H), 2.4 (s, 3H), 3.0 (s, 6H), 4.5 5-(2-trifluoromethyl-4- yl (d, 1H),5.15 (q, 1H), 6.8 (d, 1H), dimethylaminophenyl)pyrazin-2- 7.0 (s, 1H),7.1 (d, 1H), 7.2-7.4 amine (m, 5H) 17 H 1-propylbutyl 2,4- 1.0 (t, 6H),1.3-1.6 (m, 8H), 2.2 358 3,6-dimethyl-N-(1-propylbutyl)-5-dimethoxyphenyl (s, 3H), 2.35 (s, 3H), 3.75 (s, 3H),(2,4-dimethoxyphenyl)pyrazin-2- 3.85 (s, 3H), 3.9 (d, 1H), 4.25 (br,amine 1H), 6.5 (s, 1H), 6.55 (d, 1H), 7.2 (d, 1H) 18 H 1- 2,4- 1.0 (t,3H), 1.9-2.1 (m, 2H), 2.2 378 3,6dimethyl-N-(3-phenylpropyl)-5-phenylpropyl dimethoxyphenyl (s, 3H), 2.4 (s, 3H), 3.7 (s, 3H), 3.8(2,4-dimethoxyphenyl)pyrazin-2- (s, 3H), 4.5 (d, 1H), 5.15 (q, 1H),amine 6.5 (s, 1H), 6.55 (d, 1H), 7.1 (d, 1H), 7.2-7.4 (m, 5H) 19 H1-ethylpropyl 4-chloro-2- 1.0 (t, 6H), 1.4-1.6 (m, 4H), 2.1 3183,6-dimethyl-N-(1-ethylpropyl)-5- methylphenyl (s, 3H), 2.15 (s, 3H),2.4 (s, 3H), (2-methyl-4-chlorophenyl)pyrazin- 4.0-4.1 (br, 2H), 7.1 (d,1H), 7.2 2-amine (d, 1H), 7.25 (s, 1H) 20 H 1-ethylpropyl4-dimethylamino-2- 11.0 (t, 6H), 1.4-1.6 (m, 4H), 2.15 3813,6-dimethyl-N-(1-ethylpropyl)-5- trifluoromethylphen- (s, 3H), 2.35 (s,3H), 3.0 (s, 6H), (2-trifluoromethyl-4- yl 4.0 (d, 1H), 4.1 (m, 1H), 6.8(d, dimethylaminophenyl)pyrazin-2- 1H), 7.0 (s, 1H), 7.1 (d, 1H) amine20a H

2,4-dichlorophenyl 0.89 (t, 3H), 1.6 (m, 2H), 2.14 (s, 3H), 2.42 (s,3H), 3.44 (m, 2H), 4.16 (m, 1H), 7.43 (d, 1H), 7.50 (d, 1H0, 7.72 (s,1H); HCl salt 340, 2-{[5-(2,4-dimethylphenyl)-3,6- dimethylpyrazin-2-yl]amino}butan-1-ol

Example 21

[0251] [N-(1-ethyl)propyl]-3,6-dimethyl-5-(2,4,6-trimethylphenyl)pyrazine-2-amine [Formula I: Ar=2,4,6-trimethylphenyl;R₂=-N-(1-ethyl)propyl; R,=R₃=CH₃]

[0252] To a solution of5-bromo-[N-(1-ethyl)propyl]-3,6-dimethylpyrazine-2-amine (200 mg)obtained as in Example 1B in THF (4 mL) at room temperature is added[1,3-bis(diphenylphosphino)propane]dichloronickel(II) (40 mg). After 10min, 2,4,6-trimethylphenylmagnesium bromide (1.0M in THF, 4 mL) is addedslowly dropwise. The mixture is stirred at room temperature for 1 day,then refluxed overnight. The resulting dark solution is poured intoaqueous ammonium chloride and extracted twice with ether. Combinedextracts are dried (sodium sulfate), filtered, concentrated, andchromatographed to give the desired product (87 mg): ¹H NMR (CDCl₃, 400MHz) δ 1.0 (t, 6H), 1.5-1.7 (m, 4H), 1.95 (s, 3H), 2.1 (s, 3H), 2.3 (s,3H), 2.35 (s, 3H), 3.95 (br, 1H), 4.1 (br, 1H), 6.9 (s, 2H).

Example 22

[0253] 3-ethyl-[N-(1-ethyl)propyl]-6-methyl-5-(2,4,6-trimethylphenyl)pyrazine-2-amine [Formula I: Ar=2,4,6-trimethylphenyl;R₂=-N(1-ethyl)propyl; R₁═CH₂CH₃; R₃═CH₃]

[0254] To a solution of[N-(1-ethyl)propyl]-3,6-dimethyl-5-(2,4,6-trimethylphenyl)pyrazine-2-amine(74 mg; 0.24 mmol) in THF (2 mL) at 0° C. is added n-butyllithium (2.5Min hexane, 0.24 mL). After 10 min at 0° C., iodomethane (0.020 mL) isadded. The mixture is stirred at 0° C. for 10 min before being pouredinto aqueous ammonium chloride and extracted with Et₂O. The extract isdried (sodium sulfate), filtered, concentrated and the residue ispurified by preparative TLC (10% EtOAc in hexane, developed 3 times) togive the title compound (17 mg): ¹H NMR (CDCl₃, 400 MHz) δ 1.0 (t, 6H),1.25 (t. 3H), 1.5-1.7 (m, 4H), 1.95 (s, 3H), 2.05 (s, 3H), 2.3 (s, 3H),2.65 (q, 2H), 4.05 (m, 2H), 6.9 (s, 2H).

Example 23

[0255]3,6-diethyl-5-(2,4-dimethoxyphenyl)-[N-(1-ethylpropyl)]pyrazine-2-amine[Formula I: Ar=2,4-dimethoxyphenyl; R₂=-N(1-ethyl)propyl; R₁═R₃═CH₂CH₃]

[0256] 2-Chloro-3,6-diethylpyrazine (Chem. Pharm. Bull. Jap.,27, 2027(1979)) is converted to the desired product following the proceduresdescribed in Example 1: ¹H NMR (CDCl₃, 300 MHz) δ 0.95 (t, 6H), 1.15 (t,3H), 1.25 (t, 3H), 1.5-1.7 (m, 4H), 2.45 (q, 2H), 2.65 (q, 2H), 3.75 (s,3H), 3.85 (s, 3H), 4.0-4.2 (br, 2H), 6.5 (s, 1H), 6.55 (d, 1H), 7.2 (d,1H).LC-MS: 358

[0257] The Examples 24-48 in the Table II may be prepared following thegeneral procedure described in Example 23. TABLE II

EX 1HNMR MS # R_(A) R_(B) Ar (CDCl₃) (Cl) Name 23a H 1-ethylpropyl2-methoxy-4- 0.96(t,6H), 412 3,6-diethyl-N-(1-ethylpropyl)- trifluoro-1.15(t,3H), 5-(2-methoxy-4- methoxyphenyl 1.28(t,3H),trifluoromethoxyphenyl)pyrazin- 1.57(m,2H), 2-amine 1.67(m,2H),2.42(m,2H), 2.66(q,2H), 3.78(s,3H), 4.10(br,2H), 6.77(s,1H), 6.89(d,1H),7.27(d,1H) 23b H 1-ethylpropyl 4-methoxy-2- 0.96(t,6H), 4123,6-diethyl-N-(1-ethylpropyl)- trifluoro- 1.15(t,3H),5-(2-trifluoromethoxy-4- methoxyphenyl 1.27(t,3H),methoxyphenyl)pyrazin-2-amine 1.57(m,2H), 1.67(m,2H), 2.45(q,2H),2.63(q,2H), 3.85(s,3H), 4.10(br.2H), 6.86(brs, 1H),6.89 (dd,1H),7.29(d,1H) 23c H 1-ethoxypropyl 2-methoxy-4- 0.96(t,6H), 3963,6-diethyl-N-(1-ethylpropyl)- trifluoro- 1.15(t,3H), 5-(2-methoxy-4-methylphenyl 1.28(t,3H), trifluoromethylphenyl)pyrazin- 1.57(m,2H),2-amine 1.67(m,2H), 2.42(m,2H), 2.63(q,2H), 3.82(s,3H), 4.10(m,2H),7.14(s,1H), 7.28(d,1H), 7.38(d,1H) 23d H 1-ethylpropyl 4-methoxy-2-0.96(t,6H), 396 3,6-diethyl-N-(1-ethylpropyl)- trifluoro- 1.11(t,3H),5-(2-trifluoromethyl-4- methylphenyl 1.24(t,3H),methoxyphenyl)pyrazin-2-amine 1.57(m,2H), 1.67(m,2H), 2.34(q,2H),2.63(q,2H), 3.87(s,3H), 4.10(m,2H), 7.07(dd,1H), 7.24(d,1H), 7.25(s,1H)23e H 1-ethylpropyl 2-methoxy-4- 0.95(t,6H), 3423,6-diethyl-N-(1-ethylpropyl)- methyl-phenyl 1.14(t,3H), 5-(2-methoxy-4-1.28(t,3H), methylphenyl)pyrazin-2-amine 1.55(m,2H), 1.67(m,2H),2.38(s,3H), 2.46(m,2H), 2.64(q,2H), 3.75(s,3H), 4.10(m,2H), 6.74(s,1H),6.82(d,1H), 7.14(s,1H) 23f H 1-ethylpropyl 2,4-difluoro- 0.96(t,6H), 4663,6-diethyl-N-(1-ethylpropyl)- methoxyphenyl 1.17(t,3H), 5-(2,4-bis-1.27(t,3H), trifluoromethoxyphenyl)pyrazin- 1.57(m,2H), 2-amine1.69(m,2H), 2.44(m,2H), 2.64(q,2H), 4.10(m,2H), 7.20(s,1H), 7.22(d,1H),7.44(d,1H) 23g H 1-ethylpropyl 2,4-dichlorophenyl 0.96(t,6H), 3663,6-diethyl-N-(1-ethylpropyl)- 1.14(t,3H),5-(2,4-dichlorophenyl)pyrazin- 1.28(t,3H), 2-amine 1.57(m,2H),1.67(m,2H), 2.43(m,2H), 2.64(q,2H), 4.10(m,2H), 7.20(s,1H), 7.22(d,1H),7.44(d,1H) 23g H 1-ethylpropyl 2,4-dichlorophenyl 0.96(t,6H), 3663,6-diethyl-N-(1-ethylpropyl)- 1.14(t,3H),5-(2,4-dichlorophenyl)pyrazin- 1.28(t,3H), 2-amine 1.57(m,2H),1.67(m,2H), 2.43(m,2H), 2.64(q,2H), 4.12(m,2H), 7.25(d,1H), 7.30(dd,1H),7.46(d,1H) 24 H 1-methoxy-2- 2,4-dichlorophenyl 3823,6-diethyl-N-(1-methoxy-2- butyl butyl)-5-(2,4-dichlorophenyl)pyrazin-2-amine 25 H 1-methylpropyl 2,4-dichlorophenyl352 3,6-diethyl-N-(1-methylpropyl)- 5-(2,4-dichlorophenyl)pyrazin-2-amine 26 H 1-phenylethyl 2,4-dichlorophenyl 4003,6-diethyl-N-(2-phenylethyl)- 5-(2-methyl-4-chlorophenyl)pyrazin-2-amine 27 H 1-propylbutyl 4-chloro-2- 3743,6-diethyl-N-(1-propylbutyl)- methylphenyl 5-(2-methyl-4-chlorophenyl)pyrazin-2-amine 28 H 1-methoxy-2- 4-chloro-2- 3623,6-diethyl-N-(1-methoxy-2- butyl methylphenyl butyl)-5-(2-methyl-4-chlorophenyl)pyrazin-2-amine 29 H 1-methylpropyl 4-chloro-2- 3323,6-diethyl-N-(1-methylpropyl)- methylphenyl 5-(2-methyl-4-chlorophenyl)pyrazin-2-amine 30 H 1-phenylethyl 4-chloro-2- 3803,6-diethyl-N-(2-phenylethyl)- methylphenyl 5-(2-methyl-4-chlorophenyl)pyrazin-2-amine 31 H 1-propylbutyl 4-methoxy-2- 3703,6-diethyl-N-(1-propylbutyl)- methylphenyl 5-(2-methyl-4-chlorophenyl)pyrazin-2-amine 32 H 1-methoxy-2- 4-methoxy-2- 3583,6-diethyl-N-(1-methoxy-2- butyl methylphenyl butyl)-5-(2-methyl-4-methoxyphenyl)pyrazin-2-amine 33 H 1-methylpropyl 4-methoxy-2- 3283,6-diethyl-N-(1-methylpropyl)- methylphenyl 5-(2-methyl-4-methoxyphenyl)pyrazin-2-amine 34 H 1-propylbutyl 2,4- 3863,6-diethyl-N-(1-propylbutyl)- dimethoxyphenyl5-(2,4-dimethoxyphenyl)pyrazin- 2-amine 35 H 1-methoxy-2- 2,4- 3743,6-diethyl-N-(1-methoxy-2- butyl dimethoxyphenyl butyl)-5-(2,4-dimethoxyphenyl)pyrazin-2-amine 36 H 1-methylpropyl 2,4- 3443,6-diethyl-N-(1-methylpropyl)- dimethoxyphenyl5-(2,4-dimethoxyphenyl)pyrazin- 2-amine 37 H 1-phenylethyl 2,4- 3923,6-diethyl-N-(2-phenylethyl)- dimethoxyphenyl5-(2,4-dimethoxyphenyl)pyrazin- 2-amine 38 H benzyl 2,4- 3783,6-diethyl-N-benzyl-5-(2,4- dimethoxyphenyldimethoxyphenyl)pyrazin-2-amine 39 H 2-methyl-1- 2,4- 420 phenylpropyldimethoxyphenyl 40 H 1-propylbutyl 2-chloro-4- 4033,6-diethyl-N-(1-propylbutyl)- (dimethylamino) 5-(2-chloro-4- phenyldimethylaminophrnyl)pyrazin-2- amine 41 H 1-methoxy-2- 2-chloro-4- 3913,6-diethyl-N-(1-methoxy-2- butyl (dimethylamino) butyl)-5-(2-chloro-4-phenyl dimethylaminophenyl)pyrazin-2- amine 42 H 1-methylpropyl2-chloro-4- 361 3,6-diethyl-N-(1-methylpropyl)- (dimethylamino)5-(2-chloro-4- phenyl dimethylaminophenyl)pyrazin-2- amine 43 H2-methylpropyl 2-chloro-4- 361 3,6-diethyl-N-(2-methylpropyl)-(dimethylamino) 5-(2-chloro-4- phenyl dimethylaminophenyl)pyrazin-2-amine 44 H 1-phenylethyl 2-chloro-4- 409 3,6-diethyl-N-(2-phenylethyl)-(dimethylamino) 5-(2-chloro-4- phenyl dimethylphenyl)pyrazin-2-amine 45H 1-propylbutyl 4-dimethylamino- 437 3,6-diethyl-N-(1-propylbutyl)-2-(trifluoromethyl) 5-(2-trifluoromethyl-4- phenyldimethylaminophenyl)pyrazin-2- amine 46 H 1-methoxy-2- 4-dimethylamino-425 3,6-diethyl-N-(1-methoxy-2- butyl 2-(trifluoromethyl)butyl)-5-(2-trifluoromethyl-4- phenyl dimethylaminophenyl)pyrazin-2-amine 47 H 1-ethylpropyl

5-(2-methoxy-4-methylpyrimidin- 5-yl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 46b H 1-ethylpropyl

5-(2-methyl-6-methoxypyridin-3- yl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 46c H 1-ethylpropyl

5-(2-dimethylamino-6- methoxypyridin-3-yl)-3,6- diethyl-N-(1-ethylpropyl)pyrazin-2-amine 46d H 1-ethylpropyl 5-chloro-2,4-3,6-diethyl-N-(1-ethylpropyl)- dimethylphenyl 5-(2,4-dimethyl-5-chlorophenyl)pyrazin-2-amine 46e H 1-ethylpropyl 2,4-dichloro-5-3,6-diethyl-N-(1-ethylpropyl)- methylphenyl 5-(2,4-dimethyl-5-methylphenyl)pyrazin-2-amine 46f H 1-ethylpropyl

5-[2,4-dimethyl-5-(2-morpholin- 4-ylethoxy)phenyl]-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2- amine 46g H 1-ethylpropyl 2,4-dimethyl-5-3,6-diethyl-N-(1-ethylpropyl)- methoxyphenyl 5-(2,4-dimethyl-5-methoxyphenyl)pyrazin-2-amine 46h H 1-ethylpropyl 2-methyl-4- 3423,6-diethyl-N-(1-ethylpropyl)- methoxyphenyl 5-(2-methyl-4-methoxyphenyl)pyrazin-2-amine 46i H 1-ethylpropyl 2-methyl-4- 3823,6-diethyl-N-(1-ethylpropyl)- chlorophenyl 5-(2-methyl-4-chlorophenyl)pyrazin-2-amine 46j H 1-ethylpropyl

345 5-[5-(1-ethylpropylamino)-3,6- dimethylpyrazin-2-yl]-6-methoxypyridin-2(3H)-one 46k H 1-ethylpropyl

345 3-[5-(1-ethylpropylamino)-3,6- dimethylpyrazin-2-yl]-6-methoxypyridin-2(3H)-one 47 H 1-methylpropyl 4-dimethylamino- 3953,6-diethyl-N-(1-methylpropyl)- 2-(trifluoromethyl)5-(2-trifluoromethyl-4- phenyl methoxyphenyl)piperazin-2-amine 47a H

2-methoxy-4,6- dimethylphenyl 1.10(t,3H), 1.26(t,3H), 1.94(s,3H),2.33(s,3H), 2.38(m,2H), 2.67(m,2H), 3.40(s,3H), 3.42(s,3H), 3.57(m,2H),3.68(m,2H), 3.70(s,3H), 4.53(m,1H), 4.69(m,1H), 6.60(s,1H), 6.71(s,1H)388 3,6-diethyl-N-[2-methoxy-1- (methoxymethyl)ethyl]-5-(2- methoxy-4,6-dimethylphenyl)pyrazin-2-amine 47b H

2,4- dimethoxyphenyl 1.14(t,3H), 1.26(t,3H), 2.44(m,2H), 2.67(m,2H),3.40(s,6H), 3.53(m,2H), 3.66(m,2H), 3.75(s,3H), 3.82(s,3H), 4.52(m,1H),4.71(m,1H), 6.50(s,1H), 6.55(d,1H), 7.18(d,1H) 3903,6-diethyl-N-[2-methoxy-1- (methoxymethyl)ethyl]-5-(2,4-dimethoxyphenyl)pyrazin-2-amine 47c H

2,4-dichlorophenyl 1.14(t,3H), 1.29(t,3H), 2.43(b,2H), 2.66(m,2H),3.42(s,6H), 3.56(m,2H), 3.68(m,2H), 4.55(m,1H), 4.86(d,1H), 7.3(m,2H),7.48(m,1H) 398 3,6-diethyl-N-[2-methoxy-1- (methoxymethyl)ethyl]-5-(2,4-dichlorophenyl)pyrazin-2-amine 47d H

1.11(t,3H), 1.26(t,3H), 1.98(s,3H), 2.29(m,4H), 2.32(s,3H), 2.37(m,2H),2.57(m,2H), 2.66(m,2H), 3.42(s,6H), 3.54(m,6H), 3.68(m,2H), 4.0(m,2H),4.54(m,1H), 4.70(d,1H), 6.59(s,1H), 6.72(s,1H) 4873,6-dimethyl-N-[2-methoxy-1- (methoxymethyl)ethyl]-5-[2,4-dimethyl-6-(2-morpholin-4- ylethoxy)phenyl]-pyrazin-2- amine 47e H1-ethylpropyl 4-fluoro-2- 0.98(t,6H), 330 3,6-diethyl-N-(1-ethylpropyl)-methylphenyl 1.12(t,3H), 5-(2-methyl-4- 1.28(t,3H),fluorophenyl)pyrazin-2-amine 1.57(m,2H), 1.71(m,2H), 2.13(s,3H),2.40(m,2H), 2.66(m,2H), 4.1(b,2H), 6.93(m,2H), 7.15(m,1H) 47f2-methoxyethyl 2-methoxyethyl 2,4-dichlorophenyl 1.13(t,3H), 4133,6-diethyl-N,N-(2- 1.24(t,3H), methoxy)-5-(2,4- 2.5(b,2H),dichlorophenyl)pyrazin-2-amine 2.84(q,2H), 3.33(s,6H), 3.6(m,8H),7.31(m,2H), 7.49(s,1H) 47g Propyl Cyclopropyl 2,4-dichlorophenyl0.12(m,2H), 391 3,6-diethyl-N-propyl-N- methyl 0.48(m,2H),(cyclopropylmethyl)-5-(2,4- 0.91(t,3H), dichlorophenyl)pyrazin-2-amine1.05(m,1H), 1.15(m,3H), 1.3(m,3H), 1.6(m,2H), 2.5(b,2H), 2.83(m,2H),3.16(m,2H), 3.34(m,2H), 7.34(s,2H), 7.49(s,1H) 47h H 1-ethylpropyl

0.94(t,6H), 1.16(t,3H), 1.28(t,3H), 1.55(m,2H), 1.78(m,2H), 2.42(q,2H),2.62(q,2H), 3.94(s,3H), 4.01(s,3H), 4.12(m,2H), 8.2(s,1H) 3615-(2,4-dimethoxypyrimidin-5- yl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 47i H 1-ethylpropyl 2,4- 0.98(t,6H), 4643,6-diethyl-N-(1-ethylpropyl)- bis(trifluoromethyl)- 1.12(t,3H),5-(2,4-bis-trifluoromethyl-6- 6-methoxyphenyl 1.25(t,3H),methoxyphenyl)pyrazin-2-amine 2.64(m,4H), 2.29(q,2H), 2.61(q,2H),3.81(s,3H), 4.12(m,2H), 7.33(s,1H), 7.60(s,1H) 47j H

2,4-dichlorophenyl 0.5(m,8H), 1.03(m,2H), 1.1(t,3H), 1.3(t,3H),2.4(b,2H), 2.66(m,2H), 3.5(m,1H), 4.25(d,1H), 7.25(m,2H), 7.46(s,1H) 3903,6-diethyl-N- (dichlorophenyl)pyrazin-2-yl]- N¹,N¹-dimethylpropane-1,2-diamine 47k H

2,4-dichlorophenyl 1.16(t,3H), 1.28(t,3H), 1.35(d,3H), 2.25(m,2H),2.29(s,6H), 2.5(m,2H), 2.68(m,2H), 4.06(m,1H), 5.15(b,1H), 7.28(m,2H),7.47(s,1H) 381 N²-[3,6-diethyl-(5-2,4- dichlorophenyl)pyrazin-2-yl]-N¹,N¹-dimethylpropane-1,2- diamine 47l H

2,4- dimethoxyphenyl 0.48(m,8H), 1.05(m,2H), 1.12(t,3H), 1.30(t,3H),2.41(q,2H), 2.69(q,2H), 3.50(m,1H), 3.74(s,3H), 3.83(s,3H), 4.31(d,1H),6.51(s,1H), 6.56(d,1H), 7.17(d,1H) 382 3,6-diethyl-N-(dicyclopropylmethyl)-5-(2,4- dimethoxyphenyl)pyrazin-2-amine 47m H1-ethylpropyl

0.97(t,6H), 1.15(t,3H), 1.28(t,3H), 1.6(m,4H), 2.46(q,2H), 2.65(q,2H),3.91(s,3H), 3.94(s,3H), 4.07(m,2H), 6.40(d,1H), 7.50(d,1H) 3593,6-diethyl-N-(1-ethylpropyl)- 5-(2,6-dimethoxypyridin-3-yl)pyrazin-2-amine 47n H

0.44(m,8H), 1.03(m,2H), 1.12(t,3H), 1.30(t,3H), 2.44(q,2H), 2.67(q,2H),3.49(m,1H), 3.90(s,3H), 3.94(s,3H), 4.34(d,1H), 6.40(d,1H), 7.50(d,1H)383 3,6-diethyl-N- (dicyclopropylmethyl)-5-(2,6-dimethoxypyridin-3-yl)pyrazin- 2-amine 47o Propyl

2,4-dichlorophenyl 0.90(t,3H), 1.05(t,3H), 1.25(t,3H), 1.4(m,2H),1.6(m,2H), 2.30(s,6H), 2.52(m,2H), 2.80(m,2H), 3.26(m,2H), 3.5(b,2H),7.32(m,2H), 7.50(s,1H) 409 3,6-diethyl-N-propyl-N-(2-dimethylaminoethyl)-5-(2,4- dichlorophenyl)pyrazin-2-amine 47p H1-ethylpropyl 4-chloro-2- 3,6-diethyl-N-(1-ethylpropyl)- methylphenyl5-(2-methyl-4- chlorophenyl)pyrazin-2-amine 47q H 1-ethylpropyl2-chloro-4- 3,6-diethyl-N-(1-ethylpropyl)- methoxyphenyl 5-(2-methyl-4-methoxyphenyl)pyrazin-2-amine 47r H 1-ethylpropyl

3,6-diethyl-N-(1-ethylpropyl)- 5-(2-amino-4-methylpyridin-2-yl)pyrazin-2-amine 47s Ethyl 1-ethylpropyl 2,4-dichlorophenyl3,6-diethyl-N-(1-ethylpropyl)- 5-(2,4-dichlorophenyl)pyrazin- 2-amine47t H 1-ethylpropyl 2-chloro-4- 3,6-diethyl-N-(1-ethylpropyl)-trifluoromethyl 5-(2-methyl-4- phenyl cyanophenyl)pyrazin-2-amine 47u H1-ethylpropyl 4-cyano-2- 3,6-diethyl-N-(1-ethylpropyl)- methylphenyl5-(2-methyl-4- chlorophenyl)pyrazin-2-amine 47v H 1-ethylpropyl4-cyano-2- 3,6-diethyl-N-(1-ethylpropyl)- trifluoromethyl5-(2-trifluoromethyl-4- chlorophenyl)pyrazin-2-amine 47v H 1-ethylpropyl4-cyano-2- 3,6-diethyl-N-(1-ethylpropyl)- trifluoromethyl5-(2-trifluoromethyl-4- phenyl chlorophenyl)pyrazin-2-amine 47w H1-ethylpropyl 2-cyano-4- 3,6-diethyl-N-(1-ethylpropyl)- methoxyphenyl5-(2-cyano-4- methoxyphenyl)pyrazin-2-amine 47x H 1-ethylpropyl

3,6-diethyl-N-(1-ethylpropyl)- 5-(3-trifluoromethyl-5-chloropyridin-6-yl)pyrazin-2- amine 47y H 1-ethylpropyl 2-cyano-4-3,6-diethyl-N-(1-ethylpropyl)- trifluoromethyl 5-(2-cyano-4- phenyltrifluoromethylphenyl)pyrazin- 2-amine 47z Methyl 1-ethylpropyl2-chloro-4- 3,6-diethyl-N-methyl-N-(1- methoxyphenylethylpropyl)-5-(2-chloro-4- methoxyphenyl)pyrazin-2-amine 48 H1-phenylethyl 4-diethylamino- 443 3,6-diethyl-N-(2-phenylethyl)-2-(trifluoromethyl) 5-(2-trifluoromethyl-4- phenyldimethylaminophenyl)pyrazin-2- dimethylaminophenyl)pyrazin-2- amine

[0258] Example 48a

[0259] 3,6-diethyl-5-(2,4-diethoxy)phenyl-[N-(1-ethylpropyl)]pyrazine-2-amine [Formula I: Ar=2,4-diethoxyphenyl;R₂═-N(1-ethyl)propyl; R₁═R₃═CH₂CH₃]

[0260] A: To a solution of3,6-diethyl-5-(2,4-dimethoxyphenyl)-[N-(1-ethylpropyl)]pyrazine-2-amine(910 mg, 2.54 mmol) (obtained in example 23) in dichloromethane wasadded BBr₃ (1N,6 ml)at −78° C. The mixture is stirred for 10 min thengradually warmed to room temperature and stirred for 3 hr before beingpoured into ice-water and extracted with dichloromethane. The aqueouslayer was basified with sat. NaHCO₃ and extracted with dichloromethane.The combined extracts were dried (sodium sulfate), filtered,concentrated and the residue is purified by column (20% EtOAc in hexane)to give3,6-diethyl-5-(2,4-dihydroxyphenyl)-[N-(1-ethylpropyl)]pyrazine-2-amineas a yellow oil(590 mg, 71%): ¹H NMR (CDCl₃, 400 MHz) δ 0.94 (t,6H),1.30(t,3H), 1.36(t,3H), 1.57(m,2H), 1.67(m,2H), 2.62(q,2H), 2.86(q,2H),4.15(m, 2H), 6.41(d,1H), 6.51(d,1H), 7.27(d,1H). LC-MS: 330 (M+1).

[0261] B: The above yellow oil (60 mg, 0.182 mmol) was dissolved in DMF(2 ml) and alkylated with iodoethane (0.072 ml, 0.9 mmol) in thepresence of K₂CO₃ (125 mg) at 75° C. for 2 hr. The reaction mixture wasthen diluted with water and extracted with EtOAc. The extracts weredried (sodium sulfate), filtered, concentrated and the residue ispurified by column (2.5% MeOH in dichloromethane) to give the titlecompound as an oil (49 mg, 70%):¹H NMR (CDCl₃, 400 MHz) δ 0.96 (t,6H),1.13(t,3H), 1.27(m,6H), 1.42(t,3H), 1.57(m,2H), 1.67(m,2H), 2.47(m,2H),2.66(q,2H), 3.95-4.15(m, 6H), 6.49(s,1H), 6.53(d,1H), 7.15(d,1H). LC-MS:387 (M+1).

[0262] Examples 48b -48k may be prepared according to the generalprocedure described in Example 48a. TABLE IIa

EX# R₂ R₄ 1HNMR (CDCl₃) MS(Cl) Name 48b OH OCH₃ 0.95(t,6H), 1.30(t,3H),1.37(t,3H), 344 (M + 1) 3,6-diethyl-N-(1- 1.55(m,2H), 1.67(m,2H),2.64(q,2H), ethylpropyl)-5-(2-hydroxy- 2.86(q,2H), 3.82(s,3H),4.15(m,2H), 4-methoxyphenyl)pyrazin- 6.48(dd,1H), 6.59(d,1H), 7.31(d,1H)2-amine 48c OH OCH₂CH₃ 0.95(t,6H), 1.30(t,3H), 1.37(t,3H), 358 (M + 1)3,6-diethyl-N-(1- 1.42(t,3H), 1.55(m,2H), 1.67(m,2H),ethylpropyl)-5-(2-hydroxy- 2.62(q,2H), 2.87(q,2H), 4.05(q,2H),4-ethoxyphenyl)pyrazin-2- 4.10(m,2H), 6.46(dd,1H), 6.56(d,1H), amine7.30(d,1H) 48d OH OCH(CH₃)₂ 0.95(t,6H), 1.30(t,3H), 1.35(d,6H), 372(M + 1) 3,6-diethyl-N-(1- 1.37(t,3H), 1.55(m,2H), 1.67(m,2H),ethylpropyl)-5-[2-hydroxy- 2.64(q,2H), 2.87(q,2H), 4.11(m,2H), 4-(2-4.56(m,1H), 6.45(dd,1H), 6.56(d,1H), propoxy)phenyl]pyrazin-2-7.28(d,1H) amine 48e OH OCHF₂ 0.95(t,6H), 1.30(t,3H), 1.37(t,3H), 380(M + 1) 3,6-diethyl-N-(1- 1.55(m,2H), 1.69(m,2H), 2.64(q,2H),ethylpropyl)-5-(2-hydroxy- 2.86(q,2H), 4.14(m,1H), 4.18(brs. 1H),4-difluoromethoxyphenyl) 6.54(t,J=74 Hz,1H), 6.65(d,1H), pyrazin-2-amine6.78(s,1H), 7.36(d,1H) 48f OCH₃ OH 0.95(t,6H), 1.13(t,3H), 1.29(t,3H),344 (M + 1) 3,6-diethyl-N-(1- 1.55(m,2H), 1.67(m,2H), 2.45(q,2H),ethylpropyl)-5-(2-methoxy- 2.70(q,2H), 3.68(s,3H), 4.10(m,2H),4-hydroxyphenyl)pyrazin-2- 6.32(d,1H), 6.33(s,1H), 6.99(d,1H) amine 48gOCH₃ OCH₂CH₃ 0.95(t,6H), 1.14(t,3H), 1.28(t,3H), 372 (M + 1)3,6-diethyl-N-(1- 1.43(t,3H), 1.55(m,2H), 1.67(m,2H),ethylpropyl)-5-(2-methoxy- 2.46(q,2H), 2.65(q,2H), 3.74(s,3H),4-ethoxyphenyl)pyrazin-2- 4.07(q,2H), 4.10(m,2H), 6.51(d,1H), amine6.54(dd,1H), 7.15(d,1H) 48h OCH₃ OCH(CH₃)₂ 0.95(t,6H), 1.14(t,3H),1.28(t,3H), 386 (M + 1) 3,6-diethyl-N-(1- 1.33(d,6H), 1.55(m,2H),1.67(m,2H), ethylpropyl)-5-[2-methoxy- 2.46(q,2H), 2.65(q,2H),3.74(s,3H), 4-(2- 4.02(d,1H), 4.08(m,1H), 4.59(m,1H),propoxy)phenyl]pyrazin-2- 6.51(d,1H), 6.54(dd,1H), 7.15(d,1H) amine 48iOCH(CH₃)₂ OCH(CH₃)₂ 0.95(t,6H), 1.14(t,3H), 1.18(br. 6H), 414 (M + 1)3,6-diethyl-N-(1- 1.28(t,3H), 1.34(d,6H), 1.55(m,2H),ethylpropyl)-5-[2,4-bis- 1.67(m,2H), 2.46(m,2H), 2.65(q,2H),(2-propoxy)phenyl]pyrazin- 4.02(br, 1H), 4.10(m,1H), 4.34(m,1H), 2-amine4.55(m,1H), 6.48(d,1H), 6.54(dd,1H), 7.15(d,1H) 48j OCHF₂ OCHF₂0.96(t,6H), 1.16(t,3H), 1.28(t,3H), 430 (M + 1) 3,6-diethyl-N-(1-1.57(m,2H), 1.69(m,2H), 2.46(q,2H), ethylpropyl)-5-(2,4-bis- 2.63(q,2H),4.15(m,2H), difluoromethoxyphenyl) 6.51(t,J=75 Hz,1H), 6.55(t,J=74Hz,1H), pyrazin-2-amine 7.03(s,1H), 7.04(d,1H), 7.35(d,1H) 48k OH CH₃0.95(t,6H), 1.14(t,3H), 1.28(t,3H), 342 (M + 1) 3,6-diethyl-N-(1-1.55(m,2H), 1.67(m,2H), 2.38(s,3H), ethylpropyl)-5-(2-hydroxy-2.46(q,2H), 2.65(q,2H), 3.75(s,3H), 4-methoxyphenyl)pyrazin- 4.02(d,1H),4.08(m,1H), 6.74(s,1H), 2-amine 6.69(d,1H), 7.13(d,1H) 48l OCH₂CH₂OH CH₃0.95(t,6H), 1.16(t,3H), 1.25(t,3H), 372 (M + 1) 3,6-diethyl-N-(1-1.55(m,2H), 1.67(m,2H), 2.38(s,3H), ethylpropyl)-5-(2- 2.54(q,2H),2.68(q,2H), 3.74(t,2H), hydroxyethoxy-4- 4.11(m,2H), 4.22(m,2H),6.83(d,1H), methylphenyl)pyrazin-2- 6.87(s,1H), 7.07(d,1H) amine 48mOCH₂CH₂OCH₃ CH₃ 0.95(t,6H), 1.12(t,3H), 1.25(t,3H), 386 (M + 1)3,6-diethyl-N-(1- 1.55(m,2H), 1.67(m,2H), 2.36(s,3H), ethylpropyl)-5-(2-2.48(m,2H), 2.63(q,2H), 3.23(s,3H), methoxyethoxy-4- 3.58(t,2H),4.02(d,1H), 4.04(t,2H), 4.11(m, methylphenyl)pyrazin-2- 1H), 6.76(s,1H),6.83(d,1H), 7.14(d,1H) amine 48n O(CH₂)₂N(CH₃)₂ CH₃ 0.94(t,6H),1.12(t,3H), 1.25(t,3H), 399 (M + 1) 3,6-diethyl-N-(1- 1.55(m,2H),1.67(m,2H), 2.15(s,6H), ethylpropyl)-5-(2- 2.36(s,3H), 2.48(m,2H),2.58(t,2H), dimethylaminoethoxy-4- 2.63(q,2H), 4.00(t,2H), 4.02(d,1H),methylphenyl)pyrazin-2- 4.11(m,1H), 6.74(s,1H), 6.83(d,1H), amine7.14(d,1H)

Example 48o:

[0263] [N-(]-ethyl)propyl]-5-[(2-dimethylamino-4-methyl)pyridin-5-yl]-3,6-diethylpyrazine-2-amine[Formula I: Ar=(2-dimethylamino-4-methyl)pyridin-5-yl;R₂═-N(1-ethyl)propyl); R₁═R₃═CH₂CH₃]

[0264] 5-Bromo-3,6-diethyl-[N-(1-ethyl)propyl]pyrazine-2-amine obtainedin Example 23 reacts with[(2-dimethylamino-4-methyl)pyridin-5-yl]magnesium bromide as in Example21 to give the title compound.

[0265]¹H NMR (CDCl₃, 400 MHz) δ 0.96 (t,6H), 1.14(t,3H), 1.28(t,3H),1.57(m,2H), 1.67(m,2H),2.12(s,3H), 2.48(m,2H), 2.64(q,2H), 3.12(s,6H),4.10(m, 2H), 6.43(s,1H), 7.89(s,1H). LC-MS: 356

Example 49

[0266][N-(1-ethyl)propyl]-5-(2-methoxy-4,6-dimethylphenyl)-3,6-dimethylpyrazine-2-amine[Formula I: Ar=2-methoxy-4,6-dimethylphenyl; R₂═-N(1-ethyl)propyl;R₁═R₃═CH₃]

[0267] A. To a solution of 2-chloro-3,6-dimethylpyrazine (0.71 g, 5.0mmol) and tetrakis(triphenylphosphine)palladium(0) (140 mg, 2.5 mol %)in ethylene glycol dimethyl ether (30 mL) is added2-methoxy-4,6-dimethylbenzeneboronic acid (1.08 g, 6.0 mmol), followedby addition of 1 M aqueous sodium carbonate solution (15 mL). Themixture is stirred at 70-75° C. overnight, allowed to cool, diluted bysaturated aqueous sodium bicarbonate solution, and extracted twice withEtO₂. Combined extracts are dried (sodium sulfate), filtered, andconcentrated in vacuo. The residue is purified by filtration through ashort pad of silica gel to give 1.4 g of crude product.

[0268] B. The crude material obtained above is dissolved indichloromethane (20 mL), cooled to 0° C., and m-chloroperoxybenzoic acid(70%, 1.2 g) is added in portions. After 4 hours at ambient temperature,the mixture is diluted by n-hexane (20 mL) and washed with 1 M aqueoussodium hydroxide solution. The organic phase separated is dried (sodiumsulfate), filtered, concentrated in vacuo, and the residue is useddirectly in the next step without further purification.

[0269] C. The crude N-oxide is dissolved in phosphorus oxychloride (10mL) and the solution is heated at 80° C. overnight. Evaporation ofphosphorus oxychloride and usual aqueous work-up of the residue followedby chromatography on silica yields 2-aryl-5-chloro-3,6-dimethylpyrazineas a white solid (0.76 g).

[0270] D. To a solution of the chloropyrazine obtained in C (260 mg,0.94 mmol) and tris(dibenzylideneacetone)dipalladium(0) (11 mg) intoluene (10 mL) is added a 0.2 M solution of tri-tert-butylphosphine intoluene (0.10 mL). After 15 min at ambient temperature,1-ethylpropylamine (0.14 mL) and potassium t-butoxide (1.0 M in THF, 1.4mL) are added successively and the reaction mixture is heated at 80° C.for 4 hours. The mixture is allowed to cool to room temperature, dilutedby ether, washed with aqueous ammonium chloride solution, dried (sodiumsulfate), filtered, concentrated, and chromatographed on silica to givethe desired product as a white solid (250 mg): ¹H NMR (CDCl₃, 400 MHz) δ0.95 (t, 6H), 1.5-1.7 (m, 4H), 2.0 (s, 3H), 2.1 (s, 3H), 2,4 (s, 6H),3.7 (s,3H), 3.95 (br d, 1H), 4.1 (br q, 1H), 6.6 (s, 1H), 6.7 (s, 1H).

[0271] Examples 50-53 may be prepared according to the general proceduredescribed in Example 49.

Example 50

[0272]N-benzyl-5-(2-methoxy-4,6-dimethylphenyl)-3,6-diethylpyrazine-2-amine[Formula I: Ar=2-methoxy-4,6-dimethylphenyl; R₂═—NHCH₂C₆H₅);R₁═R₃═CH₂CH₃] MS (CI) 376.

Example 51

[0273]5-(2-methoxy-4,6-dimethylphenyl)-3,6-diethylpyrazine-[N-(1-phenyl-2-methyl)propyl]-2-amine[Formula I: Ar=2-methoxy-4,6-dimethylphenyl; R₂═—NHCH(C₆H₅)CH(CH₃)CH₃;R₁═R₃═CH₂CH₃] MS (CI) 418.

Example 52

[0274]5-(2-methoxy-4,6-dimethylphenyl)-3,6-diethylpyrazine-[N-(1-propyl)butyl]-2-amine

[0275] [Formula I: Ar=2-methoxy-4,6-dimethylphenyl;R₂═—NHCH(CH₂CH₂CH₃)₂; R₁═R₃═CH₂CH₃] MS (CI) 384.

Example 53

[0276] [N-(1-methoxy)-2-butyl-5-(2-methoxy-4,6-dimethylphenyl)-3,6-diethylpyrazine-2-amine[Formula I: Ar=2-methoxy-4,6-dimethylphenyl; R₂═—NCH(CH₂OCH₃)CH₂CH₃;R₁═R₃═CH₂CH₃] MS (CI) 372.

Example 54

[0277]5-(2-methoxy-2,4-dimethylphenyl)-3,6-dimethyl-2-(3-pentyloxy)pyrazine[Formula I: Ar=2-methoxy-4,6-dimethylphenyl; R₂═—OCH(CH₂CH₃)₂;R₁═R₃═CH₃]

[0278] To an suspension of NaH (60% in mineral oil, 40 mg) in DMF (0.5mL) is added 3-pentanol (0.1 mL). The mixture is stirred at ambienttemperature until hydrogen evolution Is ceased. To the resultingalkoxide solution is added an N-methylpyrrolidinone solution of2-aryl-5-chloro-3,6-dimethylpyrazine (20 mg in 0.5 mL solvent) obtainedas in Example 49C. After 1 hour at room temperature, the mixture isheated to 70° C. for another hour before it being allowed to cool anddiluted with aqueous ammonium chloride solution and extracted twice withEt₂O. Combined organics are dried (sodium sulfate), filtered,concentrated, and chromatographed on silica gel to give the titlecompound as a colorless oil (15 mg): ¹H NMR (CDCl₃, 400 MHz) δ 1.0 (t,6H), 1.75 (m, 4H), 1.95 (s, 3H), 2.15 (s, 3H), 2.35 (s, 3H), 2.45 (s,3H), 3.7 (s, 3H), 5.1 (quint, 1H), 6.6 (s, 1H), 6.7 (s, 1H): MS (CI)329, 259.

[0279] Examples 55-62 in Table III may be prepared following the generalprocedure described in Examples 54 and 63. TABLE III

MS EX# R R_(B) Ar 1H NMR (CDCl3) (Cl) NAME 55 Me

2-methoxy-4,6- dimethylphenyl 0.4 (m, 2H), 0.6 (m, 2H), 1.35 (m,1H),1.95 (s, 3H), 2.15 (s, 3H), 2.35 (s, 3H), 2.5 (s, 3H), 3.7 (s, 3H), 4.2(d, 2H), 6.6 (s, 1H), 6.7 (s, 1H) 313, 259 3,6-dimethyl-(2-cyclopropylmethoxy)-5-(2- methoxyethoxy-4,6- dimethylphenyl)pyrazine 56Me

2,4-dichlorophenyl 0.4 0.6 (m, 10H), 2.2 (s, 3H), 2.45 (s, 3H), 4.5 (t,1H), 7.25 (d, 1H), 7.3 (d, 1H), 7.5 (s, 1H) 363, 269 3,6-dimethyl-(2-dicyclopropylmethoxy)-5-(2,4- dichlorophenyl)pyrazine 57 Me

2,4-dichlorophenyl 393, 269 3,6-dimethyl-2-(1-cyclohexylpropoxy)-5-(2,4- dichlorophenyl)pyrazine 58 Me

2,4-dichlorophenyl 381, 269 3,6-dimethyl-2-(1-cyclopentylpropoxy)-5-(2,4- dichlorophenyl)pyrazine 59 Me

2,4-dichlorophenyl 393, 269 3,6-dimethyl-2-(1-cyclobutylpropoxy)-5-(2,4- dichlorophenyl)pyrazine 60 Me

2,4-dichlorophenyl 399, 269 3,6-dimethyl-2-(cyclopropylphenylmethoxy)-5- (2,4-dichlorophenyl)pyrazine 61 Me

2,4-dichlorophenyl 393, 269 3,6-dimethyl-3-(2,4- dichlorophenyl)-6-[(2-propylcyclohexyl)oxy]pyrazine 61a Et

4-fluoro-2- methylphenyl 331 3,6-dimethyl-2-(1- ethylpropoxy)-5-(2,4-dichlorophenyl)pyrazine 61b Et

2,4-dichlorophenyl 399 2-[2-methoxy-1- (methoxymethyl)ethoxy]-3,6-diethyl-5-(2-methoxy-4- trifluoromethoxyphenyl)pyra- zine 61b Et

2-methoxy-4- trifluoromethoxy phenyl 413 3,6-diethyl-2-(1-ethylpropoxy)-5-(2-methoxy-4- trifluorophenyl)pyrazine 62 Et

2,4- dimethoxyphenyl 1.0 (t, 6H), 1.2 (t, 3H), 1.25 (t, 3H), 1.75(quint, 4H), 2.5 (br, 2H), 2.9 (q, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 5.1(quint, 1H), 6.5 (s, 1H), 6.6 (d, 1H), 7.2 (d, 1H) 359, 2893,6-diethyl-2-(1-ethylpropoxy)- 5-(2,4-dimethoxyphenyl)pyrazine 62a Me

2,4-dichlorophenyl 1.9 (m, 2H), 2.1 (m, 2H), 2.23 (s, 3H), 2.34 (s, 3H),2.4 (m, 2H), 2.46 (s, 3H), 2.7 (b, 2H), 5.2 (b, 1H), 7.26 (dd, 1H), 7.33(dd, 1H), 7.48 (d, 1H) 366, 269 2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-0 methylpiperidin-4- yl)oxy]pyrazine 62b Me

2,4-dichlorophenyl 407, 269 3,6-dimethyl-2-(1- cyclohexylbutoxy)-5-(2,4-dichlorophenyl)pyrazine 62c Me

2,4-dichlorophenyl 381, 269 2,5-dimethyl-3-(2,4- dichlorophenyl)-6-[(4-methoxycyclohexyl)oxy]pyrazine 62d Me

2,4-dichlorophenyl 2.2 (m, 2H), 2.25 (s, 3H), 2.46 (s, 3H), 3.9-4.1 (m,4H), 5.6 (m, 1H), 7.26 (d, 1H), 7.33 (d, 1H), 7.49 (s, 1H) 339, 2692,5-dimethyl-3-(2,4- dichlorophenyl)-6- (tetrahydrofuran-3-yl)oxy]pyrazine 62e Me

2,4-dichlorophenyl 253, 269 2,5-dimethyl-3-(2,4- dichlorophenyl)-6-(tetrahydro-2H-pyran-4- yloxy)pyrazine 62f Me

2,4-dichlorophenyl 1.4-2.4 (m, 6H), 2.23 (s, 3H), 2.33 (s, 3H), 2.44 (s,3H), 2.7 (m, 1H), 3.1 (m, 1H), 5.3 (m, 1H), 7.26 (d, 1H), 7.31 (d, 1H),7.48 (s, 1H) 366, 269 2,5-dimethyl-3-(2,4- dichlorophenyl)-6-[(1-methylpiperidin-3- yl)oxy]pyrazine 62g Me

2,4-dichlorophenyl 380, 269 2,5-dimethyl-3-(2,4- dichlorophenyl)-6-[(1-ethylpiperidin-3- yl)oxy]pyrazine 62h Me

2,4-dichlorophenyl 366, 269 2,5-dimethyl-3-(2,4- dichlorophenyl)-6-[(1-aminopiperidin-4- yl)oxy]pyrazine 62i Me

2,4-dichlorophenyl 352, 269 2,5-dimethyl-3-(2,4-dichlorophenyl)-6-(1-piperidin- 4-yl)oxy]pyrazine 62j Me

2,4-dichlorophenyl 382, 269 2-{(3,6-dimethyl)-[5-(2,4-dichlorophenyl)pyrazin-2- yl)oxy}-N,N-diethylpropan-1- amine 62k Me

2,4-dichlorophenyl 340, 269 3-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2- yl]oxy}butylamine 62l Me

2,4-dichlorophenyl 352, 269 2,5-dimethyl-3-(2,4-dichlorophenyl)-6-(piperidin-3- yl)oxy]pyrazine 62m Me

2,4-dichlorophenyl 1.16 (t, 3H), 2.1 (m, 1H), 2.24 (s, 3H), 2.3-2.6 (m,4H), 2.46 (s, 3H), 2.8 (m, 2H), 3.0 (m, 1H), 5.5 (m, 1H), 7.26 (d, 1H),7.32 (d, 1H), 7.48 (s, 1H) 366, 269 2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1- ethylpyrrolidin-3- yl)oxy]pyrazine 62n Me

2,4-dichlorophenyl 352, 269 2,5-dimethyl-3-(2,4- dichlorophenyl)-6-[(1-methylpyrrolidin-3- yl)oxy]pyrazine 62o Me

2,4-dichlorophenyl 338, 269 2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(pyrrolidin- 3-yl)oxy]pyrazine 62p Me

2,4-dichlorophenyl 383, 269 ethyl 3-{[5-(2,4- dichlorophenyl)-3,6-dimethylpyrazin-2- yl]oxy}butanoate 62q Me

2,4-dichlorophenyl 1.14 (t, 3H), 1.26 (t, 3H), 2.05 (q, 2H), 2.19 (s,3H), 2.54 (s, 3H), 4.22 (q, 2H), 5.12 (t, 1H), 7.25 (d, 1H), 7.33 (d,1H), 7.48 (s, 1H) 383, 269 ethyl 2-{[5-(2,4- dichlorophenyl)-3,6-dimethylpyrazin-2- yl]oxy}propanoate 62r Me

2,4-dichlorophenyl 2.44 (s, 3H), 2.64 (s, 3H), 6.53 (d, 2H), 7.32 (d,1H), 7.43 (d, 1H), 7.56 (s, 1H), 7.70 (d, 2H) 346, 2692,5-dimethyl-3-(2,4- dichlorophenyl)-6-(pyridin-4- yl)oxy]pyrazine 62sEt

2-methoxy-4,6- dimethylphenyl 0.98 (t, 6H), 1.11 (t, 3H), 1.23 (t, 3H),1.75 (m, 4H), 1.96 (s, 3H), 2.35 (s, 3H), 2.4 (m, 2H), 2.8 (m, 2H), 3.70(s, 3H), 5.1 (m, 1H), 6.60 (s, 1H) 6.71 (s, 1H) 357, 2873,6-diethyl-2-(1-ethylpropoxy)- 5-(2-methoxy-4,6-dimethylphenyl)pyrazine 62t Me

2,4-dichlorophenyl 0.97 (t, 6H), 1.74 (m, 4H), 2.24 (s, 3H), 2.44 (s,3H), 5.11 (m, 1H), 7.28 (s, 1H), 7.32 (d, 1H), 7.48 (s, 1H) 340, 2693,6-dimethyl-2-(1- ethylpropyl)-5-(2,4- dichlorophenyl)pyrazine 62u Et

2-hydroxy-4,6- dimethylphenyl 0.98 (m, 6H), 1.12 (t, 3H), 1.21 (t, 3H),2.74 (m, 4H), 2.01 (s, 3H), 2.29 (s, 3H), 2.5 (m, 2H), 2.73 (m, 2H),5.14 (m, 1H), 6.4 (b, 1H), 6.58 (s, 1H), 6.65 (s, 1H) 343, 2733,6-diethyl-2-(1-ethylpropoxy)- 5-(2-hydroxy-4,6-dimethylphenyl)pyrazine 62v Et

2,4-dichlorophenyl 0.99 (t, 6H), 1.16 (t, 3H), 1.24 (t, 3H), 1.75 (m,4H), 2.5 (b, 2H), 2.82 (m, 2H), 5.13 (m, 1H), 7.26 (d, 1H), 7.32 (d,1H), 7.49 (s, 1H) 367, 297 3,6-diethyl-2-(1-ethylpropoxy)-5-(2,4-dichlorophenyl)pyrazine 62w Et

0.99 (t, 6H), 1.15 (t, 3H), 1.23 (t, 3H), 1.72 (m, 4H), 1.99 (s, 3H),2.25 (m, 4H), 2.32 (s, 3H), 2.4 (m, 2H), 2.55 (m, 2H), 2.8 (m, 2H), 2.56(m, 4H), 4.0 (m, 2H), 5.14 (m, 1H), 6.57 (s, 1H), 6.71 (s, 1H) 456, 3863,6-diethyl-2-(1-ethylpropoxy)- 5-[2,4-dimethyl-6-(2-morpholin-4-ylethoxy)phenyl]pyrazine 62x Et

2,4- bis(trifluoromethyl) phenyl 3,6-diethyl-2-(1-ethylpropoxy)-5-(2,4-bis- trifluoromethylphenyl)pyrazine 62y Et

2-chloro-4- trifluoromethyl phenyl 3,6-diethyl-2-(1-ethylpropoxy)-5-(2-chloro-4- trifluorophenyl)pyrazine 62z Et

3,6-diethyl-2-(1-ethylpropoxy)- 5-(2-methoxy-4-methylpyridin-3-yl)pyrazine

Example 63

[0280] [N-(1 -ethyl)propyl] -3,6-dimethyl-5-{2-[2-(4-morpholino)ethyl]oxy-4,6-dimethylphenyl}pyrazine-2-amine [FormulaI: Ar=2-[2-(4-morpholino)ethyl]oxy-4,6-dimethylphenyl;R₂═—NHCH(CH₂CH₃)₂; R₁═R₃═CH₃]

[0281] A. A solution of2-chloro-3,6-dimethyl-5-(2-methoxy-4,6-dimethylphenyl)pyrazine (180 mg)in dichloromethane was cooled to 0° C. and boron tribromide (0.1 mL) isadded slowly dropwise. After the addition, the mixture is furtherstirred at 0° C. for 1.5 hours, diluted by Et₂O, washed with saturatedaqueous sodium bicarbonate solution, dried (sodium sulfate), filtered,and concentrated in vacuo. The residue is used in the next step withoutfurther purification.

[0282] B. To a suspension of the crude phenol and potassium carbonate(400 mg) in DMF (4 mL) is added 4-(2-chloroethyl)morpholinehydrochloride (200 mg) in one portion and the mixture is stirred at 60°C. for 4 hours. After further stirring at room temperature overnight,the mixture is poured into aqueous sodium bicarbonate and extractedtwice with Et2O -hexane. Combined extracts are dried (sodium sulfate),filtered, concentrated, and chromatographed on silica (eluent 15 5%triethylamine in 1 :1 EtOAc - hexane) to give the product as a colorlessoil (160 mg).

[0283] C. The chloropyrazine is converted to the correspondingaminopyrazine following the same procedure as in Example 49D: ¹H NMR(CDCl₃, 400 MHz) δ 0.95 (m, 6H), 1.6 (m, 4H), 2.0 (s, 3H), 2.1 (s, 3H),2.3 (m, 4H), 2.35 (s, 6H), 2.6 (m, 2H), 3.6 (m, 2H), 3.9 (d, 1H), 4.0(m, 2H), 4.05 (m, 1H), 6.55 (s, 1H), 6.7 (s, 1H); MS (CI) 427.

[0284] Examples 64-74 in Table IV may be prepared following the generalprocedure described in Example 63. TABLE IV

EX# R R_(A) R_(B) 1H NMR (CDCI3) MS (CI) NAME 64 Me H 1-propylbutyl0.95(t, 6H), 1.3-1.6(m, 8H), 2.0(s, 455 3,6-dimethyl-N-(1- 3H), 2.1(s,3H), 2.3(m, 10H), 2.6(m, propylbutyl)-5-[2,4-dimethyl- 2H), 3.6(m, 4H),3.85(d, 1H), 4.0(m, 6-(2-morpholin-4- 2H), 4.25 (m, 1H), 6.6(s, 1H),6.7(s, ylethoxy)phenyl]pyrazine-2- 1H) amine 65 Me H 1-methoxy-2- 1.0(t,2H), 1.8(m, 2H), 2.0(s, 3H), 443 3,6-dimethyl-N-(1-methoxy-2- butyl2.1(s, 3H), 2.3(m, 10H), 2.6(br, 2H), butyl)-5-[2,4-dimethyl-6-(2-3.4(s, 3H), 3.5-3.6(m, 6H), 4.0(br, morpholin-4-ylethoxy) 2H), 4.25(br,1H), 4.4(d, 1H), 6.6(s, phenyl]pyrazine-2-amine 1H), 6.7(s, 1H) 66 Mepropyl propyl 0.9(t, 6H), 1.6(q, 4H), 2.0(s, 3H), 4413,6-dimethyl-N,N-dipropyl-5- 2.15(s, 3H), 2.3(m, 4H), 2.35(s,[2,4-dimethyl-6-(2-morpholin- 3H), 2.45(s, 3H), 2.55(m, 2H), 3.24-ylethoxy)phenyl]pyrazine-2- (m, 4H), 3.6(m, 4H), 4.0(m, 2H), 6.6 amine(s, 1H), 6.7(s, 1H) 67 Et H 1-ethylpropyl 0.95(m, 6H), 1.1(t, 3H),1.25(t, 3H), 455 3,6-diethyl-N-(1-ethylpropyl)- 1.5-1.7(m, 4H), 2.0(s,3H), 2.25(m, 5-[2,4-dimethyl-6-(2- 4H), 2.3(s, 3H), 2.35(q, 2H), 2.55morpholin-4- (m, 2H), 2.6(q, 2H), 3.55(m, 4H), 4.0ylethoxy)phenyl]pyrazine-2- (m, 3H), 4.1(m, 1H), 6.6(s, 1H), 6.7 amine(s, 1H) 68 Et H 1-propylbutyl 0.95(t, 6H), 1.1(t, 3H), 1.2(t, 3H), 4833,6-diethyl-N-(1-propylbutyl)- 1.4(br, 4H), 1.55(br, 4H), 2.0(s, 3H),5-[2,4-dimethyl-6-(2- 2.25(m, 4H), 2.3(s, 3H), 2.35(q, morpholin-4- 2H),2.55(br s, 2H), 2.6(q, 2H), 3.6 ylethoxy)phenyl]pyrazine-2- (br s, 4H),4.0(br, 3H), 4.25(br q, amine 1H), 6.6(s, 1H), 6.7(s, 1H) 69 Et propylpropyl 0.9(t, 6H), 1.1(t, 3H), 1.3(t, 3H), 1.6 4693,6-diethyl-N,N-dipropyl-5- (m, 4H), 2.0(s, 3H), 2.25(br, 4H), 2.3[2,4-dimethyl-6-(2-morpholin- (s, 3H), 2.4(m, 2H), 2.55(br s, 2H),4-ylethoxy)phenyl]pyrazine-2- 2.7-2.9(m, 2H), 3.2(m, 4H), 3.6(m, amine4H), 4.0(m, 2H), 6.6(s, 3H), 6.7(s, 1H) 70 Et ethyl butyl 0.9(t, 3H),1.1-1.3(m, 9H), 1.3(m, 469 3,6-diethyl-N-ethyl-N-propyl- 2H), 1.55(m,2H), 2.0(s, 3H), 2.25 5-[2,4-dimethyl-6-(2- (br, 4H), 2.3(s, 3H), 2.4(m,2H), 2.55 morpholin-4-ylethoxy) (br s, 2H), 2.7-2.9(m, 2H), 3.2(m,phenyl]pyrazine-2-amine 4H), 3.6(m, 4H), 4.0(m, 2H), 6.6(s, 3H), 6.7(s,1H) 71 Et H 1-methylpropyl 1.0(t, 3H), 1.1(t, 3H), 1.2(t + d, 6H), 4413,6-diethyl-N-(1- 1.5-1.7(m, 2H), 2.0(s, 3H), 2.25(brmethylpropyl)-5-[2,4-dimethyl- s, 4H), 2.3(s, 3H), 2.35(q, 2H), 2.556-(2-morpholin-4- (br s, 2H), 2.6(q, 2H), 3.55(app t,ylethoxy)phenyl]pyrazine-2- 4H), 4.0(m, 3H), 4.2(m, 1H), 6.6(s, amine1H), 6.7(s, 1H) 72 Et H 1-methoxy-2- 1.0(t, 3H), 1.1(t, 3H), 1.3(t, 3H),1.7 471 3,6-diethyl-N-(1-methoxy-2- butyl (br, 2H), 2.0(s, 3H), 2.25(brs, 4H), butyl)-5-[2,4-dimethyl-6-(2- 2.3(s, 3H), 2.35(q, 2H), 2.55(br s,morpholin-4- 2H), 2.6(q, 2H), 3.4(s, 3H), 3.6(br s,ylethoxy)phenyl]pyrazine-2- 6H), 4.0(br, 2H), 4.25(br, 1H), 4.45 amine(d, 1H), 6.6(s, 1H), 6.7(s, 1H) 73 Et propyl cyclopropane- 0.1(app d,2H), 0.45(app d, 2H), 0.9 481 3,6-diethyl-N-(1-methoxy-2- methyl (t,3H), 1.05(m, 1H), 1.1(t, 3H), 1.2 butyl)-5-[2,4-dimethyl-6-(2- (t, 3H),2.0(s, 3H), 2.25(m, 4H), 2.3 morpholin-4- (s, 3H), 2.4(m, 2H), 2.55(brs, 2H), ylethoxy)phenyl]pyrazine-2- 2.8(m, 2H), 3.1(d, 2H), 3.3(m, 2H),amine 3.6(br s, 4H), 4.0(br, 2H), 6.6(s, 1H), 6.7(s, 1H) 74 Et ethylbenzyl 1.0-1.3(m, 9H), 2.0(s, 3H), 2.25(br 5033,6-diethyl-N-ethyl-N-benzyl- s, 4H), 2.3(s, 3H), 2.4(m, 2H), 2.555-[2,4-dimethyl-6-(2- (br s, 2H), 2.8(m, 2H), 3.25(q, 2H),morpholin-4-ylethoxy) 3.6(br s, 4H), 4.0(br, 2H), 4.45(appphenyl]pyrazine-2-amine q, 2H), 6.6(s, 1H), 6.7(s, 1H), 7.25 (m, 1H),7.3(t, 2H), 7.4(d, 2H)

Example 75

[0285]3-bromo-6-chloro-5-(2,4-dichlorophenyl)-[N-(I-ethyl)propyl]pyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R₁═Br; R₂═—NHCH(CH₂CH₃)₂; R₃═Cl]

[0286] A. A solution of 2,6-dichloropyrazine (2.2 g) and1-ethylpropylamine (5 mL) in EtOH (10 mL) is heated at 140° C. in aTeflon-sealed tube. Resulting solution is concentrated in vacuo, dilutedby water, and extracted twice with hexane-ethyl ether. Combined extractsare dried (sodium sulfate), filtered, concentrated in vacuo, and theresidue is filtered through a short pad of silica gel. The filtrate isconcentrated to give 2-(3-pentylamino)-6-chloropyrazine as brownish oilthat solidifies on standing (3.0 g).

[0287] B. A solution of the above amine (4.09 g; 20.48 mmol) inchloroform (80 ml) is cooled to 0° C. and N-bromosuccinimide (3.65 g;20.48 mmol) is added in portions. The mixture is stirred at 0° C. for 30min, poured into saturated aqueous NaHCO₃, and extracted withdichloromethane. The combined extracts are washed successively withwater and brine, dried (sodium sulfate), and concentrated in vacuo. Theresidue is chromatographed on silica gel (6% EtOAc in hexane) to givethe desired 3-bromopyrazine as a minor product (0.53 g; 9%) along with6-chloro-5-bromo-[N-(1-ethyl)propyl]pyrazine-2-amine (4.37 g; 77%) asthe major isomer.

[0288] C. 5-bromopyrazine obtained as above undergoes Suzuki couplingwith 2,4-dichlorobenzeneboronic acid following the procedures in Example1C to give 6-chloro-5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]pyrazine-2-amine.

[0289] D. The aryl pyrazine is brominated again by usingN-bromosuccinimide as described in Example 75B to give the desiredproduct: ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t, 6H), 1.58 (m,2H), 1.70(m,2H), 4.00 (m,1H), 5.20 (d,1H), 7.30 (s, 2H), 7.50 (s,1H); MS(CI) 422.

Example 76

[0290]6-chloro-5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]-3-(2-propenyl)pyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R₁═CH₂CH═CH₂; R₂═—NHCH(CH₂CH₃)₂;R₃═Cl]

[0291] The bromopyrazine obtained in Example 75 is converted to thedesired product by using allylboronic acid following the same procedureas in Example 1C: ¹H NMR (CDCl₃, 400 MHz) δ 0.93 (t, 6H), 1.50-1.71 (m,4H), 3.50 (d, 2H), 4.05 (m, 1H), 4.55 (d, 1H), 5.22 (m, 2H), 5.92 (m,1H), 7.34 (m, 2H), 7.48 (m, 1H); MS(CI) 384.

Example 77

[0292]6-chloro-5-(2,4-dichlorophenyl)-3-ethyl-[N-(1-ethyl)propyl]pyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R₁═CH₂CH₃; R₂═—NHCH(CH₂CH₃)₂; R₃═Cl]

[0293] The bromopyrazine obtained in Example 75 is converted to thedesired product by using ethaneboronic acid following the same procedureas in Example 1C: ¹H NMR (CDCl₃, 400 MHz) δ 0.96 (t, 6H), 1.30 (t, 3H),1.56 (m, 2H), 1.70 (m, 2H), 2.65 (t, 2H), 4.08 (m, 1H), 4.35 (d, 1H),7.32 (d, 1H), 7.33 (s, H), 7.48 (d, 1H); MS (CI) 372.

Example 78

[0294]5-(2,4-dichlorophenyl)-6-ethyl-[N-(1-ethyl)propyl]pyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R₁═H; R₂═—NHCH(CH₂CH₃)₂; R₃═CH₂CH₃]

[0295] A. 6-chloro-[N-(1-ethyl)propyl]pyrazine-2-amine obtained inExample 75A reacts with ethylmagnesium bromide as in Example 21 to give6-ethyl-[N-(1-ethyl)propyl]pyrazine-2-amine.

[0296] B. The above amine is brominated and coupled with2,4-dichlorobenzeneboronic acid following the same procedure asdescribed in Examples 75B and 75C, respectively to give the titlecompound: ¹H NMR (CDCl₃, 400 MHz) 6 0.97 (t, 6H), 1.13 (t,3H), 1.56(m,2H), 1.65 (m,2H), 2.45 (m,2H), 3.72 (m,1H), 4.45 (d,1H), 7.25 (d,1H), 7.30 (dd,1H), 7.48 (d,1H), 7.74 (s,1H); MS(CI) 338.

Example 79

[0297]3-bromo-5-(2,4-dichlorophenyl)-6-ethyl-[N-(1-ethyl)propyl]pyrazine-2-amine[Formula I: Ar-2,4-dichlorophenyl; R₁═Br; R₂═—NHCH(CH₂CH₃)₂; R₃═CH₂CH₃]

[0298] The product of Example 78 is brominated as in Example 75B to givethe title compound: ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t, 6H), 1.14 (t,3H), 1.56 (m, 2H), 1.65 (m, 2H), 2.45 (m, 2H), 4.02 (m, 1H), 5.00 (d,1H), 7.25 (d, 1H), 7.30 (dd, 1H), 7.46 (d, 1H); MS (CI) 416.

[0299] Examples 80-82 in Table V may be prepared following the generalprocedure described in Example 79 using the corresponding halogenatingagent indicated in the table. TABLE V

EX# X Reagent 1H NMR MS(CI) NAME 80 F SelectFluor(TM) 0.96(t, 6H),1.13(t, 3H), 1.50-1.72(m, 4H), 356 3-fluoro-6-ethyl-N-(1- 2.42(m, 2H),4.05(m, 1H), 4.60(d, 1H), 7.24 ethylpropyl)-5-(2,4- (d, 1H), 7.30(dd,1H), 7.48(d, 1H). dichlorophenyl)pyrazin-2-amine 81 ClN-chlorosuccinimide 0.97(t, 6H), 1.14(t, 3H), 1.55(m, 2H), 1.70(m, 3723-chloro-6-ethyl-N-(1- 2H), 2.46(m, 2H), 4.05(m, 1H), 4.93(d, 1H),ethylpropyl)-5-(2,4- 7.24(d, 1H), 7.30(dd, 1H), 7.47(d, 1H).dichlorophenyl)pyrazin-2-amine 82 I N-iodosuccinimide 0.97(t, 6H),1.14(t, 3H), 1.55(m, 2H), 1.68(m, 464 3-iodo-6-ethyl-N-(1- 2H), 2.43(m,2H), 4.00(m, 1H), 4.95(d, 1H), ethylpropyl)-5-(2,4- 7.24(d, 1H),7.30(dd, 1H), 7.46(d, 1H). dichlorophenyl)pyrazin-2-amine

Example 83

[0300]5-(2,4-dichlorophenyl)-6-ethyl-[N-(1-ethyl)propyl]-3-methoxypyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R₁═OCH₃; R₂═—NHCH(CH₂CH₃)₂;R₃═CH₂CH₃]

[0301] To a 1 N solution of sodium methoxide in N-methylpyrrolidinone isadded 3-bromo-6-ethyl-5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]pyrazine-2-amine obtained as in Example 79. The mixture is heated to 70°C. for 6 hr before being allowed to cool and diluted with water and thereaction mixture is extracted with 20% EtOAc in hexane. The combinedextracts are washed with water, dried (sodium sulfate), filtered,concentrated in vacuo, and chromatographed on silica gel to give thetitle compound: ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t, 6H), 1.12 (t,3H),1.56 (m, 2H), 1.65 (m, 2H), 2.40 (q, 2H), 3.92 (s, 3H), 4.04 (m, 1H),4.82 (d, 1H), 7.28 (m, 2H), 7.48 (d, 1H); MS(CI) 368.

Example 84

[0302]5-(2,4-dichlorophenyl)-3-ethyl-6-methyl-[N-(1-ethyl)propyl]pyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R₁═CH₂CH₃; R₂═—NHCH(CH₂CH₃)₂; R₃═CH₃]

[0303] A: To a solution of 2-(3-pentylamino)-6-chloropyrazine (4.26 g,21.3 mmol) (obtained in example 75) in THF (30 mL) at room temperatureis added [1,3-bis(diphenylphosphino)propane]dichloronickel(II) (540 mg).After 10 min, methylmagnesium bromide (3.0M in diethyl ether, 15.7 mL)is added slowly dropwise at 0° C. The mixture is stirred at roomtemperature for 1 hr. The resulting dark solution is poured into aqueousammonium chloride and extracted twice with ether. Combined extracts aredried (sodium sulfate), filtered, concentrated, and chromatographed togive the desired product as a light brown oil(98%).

[0304] B: A solution of the above oil in chloroform(60 mL) is cooled to0° C. and N-bromosuccinimide (3.8 g) is added in portions. After theaddition, the mixture is further stirred for 1 h while being allowed towarm to room temperature. The mixture is then concentrated to a smallvolume in vacuo, triturated with hexane, filtered, washed with hexane,and the filtrate is concentrated and chromatographed on silica gel (8%ethyl acetate in hexane elution) to give5-bromo-[N-(1-ethyl)propyl]-6-methylpyrazine-2-amine (92%).

[0305] C. A mixed solution of the above bromide (1.2 g; 4.65 mmol) andtetrakis(triphenylphosphine)palladium(0) (4 mol %) in ethyleneglycoldimethyl ether (60 mL) is stirred at room temperature for 15 min, when2,4-dichlorobenzeneboronic acid (1.3 g, 7 mmol) 5 and an aqueoussolution of sodium carbonate (1.0M, 12 mL) are added sequentially. Themixture is heated to 75° C. with stirring for 1.5 h, then diluted with0.1N sodium hydroxide and extracted twice with 1:1 hexane-ethyl ether.Combined extracts are dried (sodium sulfate), filtered, concentrated,and chromatographed on silica (4:1 hexane-EtOAc) to give5-(2,4-dichlorophenyl)-6-methyl-[N-(1-ethyl)propyl]pyrazine-2-amine as ayellow oil (1.46 g, 97%): 1H NMR (CDCl₃, 400 MHz) δ 0.97 (t,6H),1.54(m,2H), 1.67(m,2H), 2.22(s,3H), 3.65(m,1H), 4.50(br, 1H),7.27(d,1H), 7.31(dd,1H), 7.48(d,1H), 7.76(s,1H).

[0306] D: A solution of the above oil (1.27 g, 3.92 mmol) inchloroform(40 mL) is cooled to 0° C. and N-bromosuccinimide (770 mg) isadded in portions. After the addition, the mixture is further stirredfor 1 h while being allowed to warm to room temperature. The mixture isthen concentrated to a small volume in vacuo, triturated with hexane,filtered, washed with hexane, and the filtrate is concentrated andchromatographed on silica gel (3% ethyl acetate in hexane elution) togive3-bromo-5-(2,4-dichlorophenyl)-6-methyl-[N-(1-ethyl)propyl]pyrazine-2-amine(1.56 g, 98%).

[0307] E: A mixed solution of3-bromo-5-(2,4-dichlorophenyl)-6-methyl-[N-(1-ethyl)propyl]pyrazine-2-amine(960 mg; 2.38 mmol) and tetrakis(triphenylphosphine)palladium(1) (4 mol%) in ethyleneglycol dimethyl ether (25 mL) is stirred at roomtemperature for 15 min, when ethaneboronic acid (1.0 g) and an aqueoussolution of sodium carbonate (1.0M, 8.5 mL) are added sequentially. Themixture is heated to 75° C. with stirring for 12 h, then diluted with0.1 N sodium hydroxide and extracted twice with 1:1 hexane-ethyl ether.Combined extracts are dried (sodium sulfate), filtered, concentrated,and chromatographed on silica (10:1 hexane-EtOAc) to give the titlecompound as a yellow oil (460 mg, 55%): 1H NMR (CDCl₃, 400 MHz) δ 0.95(t, 6H), 1.28(t, 3H), 1.54(m, 2H), 1.67(m, 2H), 2.20(s, 3H), 2.65(q,2H), 4.13(m, 2H), 7.27(d, 1H), 7.31(d, 1H), 7.48(s, 1H).LC-MS: 352(M+1).

Example 84a

[0308]5-(2,4-dichlorophenyl)-3-ethoxy-6-ethyl-[N-(1-ethyl)propyl]pyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R₁═OCH₂CH₃; R₂═—NHCH(CH₂CH₃)₂;R₃═CH₂CH₃]

[0309] The same reaction as in Example 83 with sodium ethoxide gives thetitle compound: ¹H NMR (CDCl₃, 400 MHz)) δ 0.95 (t, 6H), 1.10 (t, 3H),1.37 (t, 3H), 1.55 (m, 2H), 1.68 (m, 2H), 2.36 (m, 2H), 4.05 (m, 1H),4.33 (q, 2H), 4.81 (d, 1H), 7.24 (d, 1H), 7.26 (dd, 1H), 7.46 (d, 1H);MS(CI) 382.

Example 85

[0310]5-(2,4-dichlorophenyl)-6-ethyl-[N-(1-ethyl)propyl]-3-methylpyrazine-2-amine[Formula J: Ar=2,4-dichlorophenyl; R₁═CH₃; R₂═—NHCH(CH₂CH₃)₂; R₃═CH₂CH₃]

[0311] 3-Bromo-5-(2,4-dichlorophenyl)-6-ethyl-[N-(1-ethyl)propyl]pyrazine-2-amine obtained from Example 79 is converted to the titlecompound by using methylmagnesium bromide according to the sameprocedure used in Example 21: ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t, 6H),1.12 (t, 3H), 1.56 (m, 2H), 1.65 (m,2H), 2.35 (s, 3H), 2.42 (m, 2H),4.04 (m, 2H), 7.25 (d, 1H), 7.29 (dd, 1H), 7.46 (d, 1H); MS (CI) 352.

Example 86

[0312]3-Bromo-5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]-6-methoxypyrazine-2-amine[Formula I: Ar-2,4-dichlorophenyl; R₁═Br; R₂═—NHCH(CH₂CH₃)₂; R₃═OCH₃]

[0313]6-Chloro-5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]pyrazine-2-amineobtained in 2 5 Example 75C is converted to5-(2,4-dichlorophenyl)-6-methoxy-[N-(1-ethyl)propyl]pyrazine-2-amineaccording to the same procedure used in Example 83, which is furtherconverted to the title compound according to the same procedure used inExample 79: ¹H NMR (CDCl₃, 400 MHz) δ 0.97 (t, 6H), 1.60 (m, 2H), 1.70(m, 2H), 3.89 (s, 3H), 3.92 (m, 1H), 4.98 (d, 1H), 7.27 (dd, 1H), 7.34(d, 1H), 7.44 (d, 1H); MS (CI) 418.

Example 86a

[0314]5-(2,4-Dichlorophenyl)-[N-(1-ethyl)propyl]-3,6-dimethoxypyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R₁═R₃═OCH₃, R₂═—NHCH(CH₂CH₃)₂]

[0315] To a solution of3-bromo-5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]-6-methoxypyrazine-2-amine(0.8 mmole, obtained in example 86) in 1-methyl-2-pyrrolidinone (5 ml)was added sodium methoxide (3.0 mmole). The resulting mixture was thenheated to 80° C. for three days. The mixture was then diluted with waterand extracted with ethyl acetate. The combined extracts were washedthoroughly with water, then brine and dried. After solvent removed, thecrude was purified by silica gel column (eluted with 3% EtOAc in hexane)to give the title compound as a light yellow oil (65% yield). ¹H NMR(CDCl₃, 400 MHz) δ 0.97 (t, 6H), 1.56 (m, 2H), 1.68 (m, 2H), 3.86 (s,3H), 3.94 (s,3H), 3.95(m, 1H), 4.82 (d, 1H), 7.27 (dd, 1H), 7.40 (d,1H), 7.44 (d, 1H). MS (CI) 370.

Example 86b

[0316]3-Ethyl-5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]-6-methoxypyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R₁═CH₂CH₃; R₃═OCH₃,R₂═—NHCH(CH₂CH₃)₂]

[0317] A: To a solution of 2-(3-pentylamino)-6-chloropyrazine (3.3 g,16.5 mmol) (obtained in example 75) in 1-methyl-2-pyrrolidinone (15 mL)at room temperature is added a solution of sodium methoxide in methanol(5.0M, 10 ml). The resulting solution was heated to 50° C. for 20 h thenevaporated and poured into water and extracted twice with ethylacetate/hexane (1:1). Combined extracts were dried (sodium sulfate),filtered, concentrated, and chromatographed to giveN-(1-ethyl)propyl-6-methoxypyrazine-2-amine as a light yellowsolid(98%).

[0318] B: A solution of the above solid in chloroform(60 mL) is cooledto 0° C. and N-bromosuccinimide (3.0 g) is added in portions. After theaddition, the mixture is further stirred for 1 h while being allowed towarm to room temperature. The mixture is then diluted withdichloromethane, washed with saturated NaHCO₃, water, brine and dried,filtered. The filtrate is concentrated and chromatographed on silica gel(dichloromethane/hexane 1:1 elution) to give3-bromo-[N-(1-ethyl)propyl]-6-methoxypyrazine-2-amine as a yellowoil(35%).¹H NMR (CDCl₃, 400 MHz) δ 0.93 (t, 6H), 1.56 (m, 2H), 1.66 (m,2H), 3.87 (s, 3H), 3.92(m, 1H), 4.85 (d, 1H), 7.18 (s, 1H).

[0319] C: To a solution of above3-bromo-[N-(1-ethyl)propyl]-6-methoxypyrazine-2-amine (1.27 g, 4.63mmol) in THF (30 mL) is added[1,3-bis(diphenylphosphino)propane]dichloronickel(II) (125 mg). After 10min, ethylmagnesium bromide (1.0M in THF, 9.7 mL) is added slowlydropwise at 0° C. The mixture is stirred at room temperature for 1 hr.The resulting dark solution is poured into aqueous ammonium chloride andextracted twice with ether. Combined extracts are dried (sodiumsulfate), filtered, concentrated, and chromatographed (2.5% MeOH/CH₂Cl₂)to give the desired product3-ethyl-[N-(1-ethyl)propyl]-6-methoxypyrazine-2-amine as a light yellowoil (55%).

[0320] D: A solution of the above oil (0.55 g, 2.46 mmol) inchloroform(10 mL) is cooled to 0° C. and N-bromosuccinimide (445 mg) isadded in portions. After the addition, the mixture is further stirredfor 30 min while being allowed to warm to room temperature. The mixtureis then concentrated to dryness in vacuo, and chromatographed on silicagel (5% ethyl acetate in hexane elution) to give5-bromo-3-ethyl-6-methoxy-[N-(1-ethyl)propyl]pyrazine-2-amine (85%).

[0321] E. A mixed solution of the above bromide (100 mg; 0.33 mmol) andtetrakis(triphenylphosphine)palladium(0) (5 mol %) in ethyleneglycoldimethyl ether (3 mL) is stirred at room temperature for 15 min, when2,4-dichlorobenzeneboronic acid (95 mg) and an aqueous solution ofsodium carbonate (1.0M, 0.75 mL) are added sequentially. The mixture isheated to 75° C. with stirring for 15 h, then diluted with water andextracted twice with 1:1 hexane-ethyl ether. Combined extracts are dried(sodium sulfate), filtered, concentrated, and chromatographed on silica(6% ethyl acetate in hexane) to give the title compound as a yellow oil(121 mg, 99%): 1H NMR (CDCl₃, 400 MHz) δ 0.97 (t,6H), 1.27(t,3H),1.56(m,2H), 1.70(m,2H), 2.62(q,2H), 3.85(s,3H), 4.00(m, 1H), 4.18(d,1H), 7.28(d,1H), 7.38(d,1H), 7.44(s,1H). MS: 368.

[0322] Examples 86C-86D in Table VI may be prepared following thegeneral procedure described in Example 86b or Example 86e using thecorresponding phenylboronic acids TABLE VI

EX# R₂ R₄ ¹H NMR MS(CI) NAME 86C OCH₃ OCH₃ 0.96(t, 6H), 1.27(t, 3H),1.56(m, 2H), 1.70(m, 2H), 360 3-ethyl-6-methoxy-N-(1- 2.62(q, 2H),3.78(s, 3H), 3.82(s, 3H), 3.85(s, 3H), ethylpropyl)-5-(2,4- 4.02(m, 2H),6.54(d, 1H), 6.56(dd, 1H), 7.26(d, 1H). dimethoxyphenyl)pyrazin-2- amine86D OCF₃ OCH₃ 0.97(t, 6H), 1.27(t, 3H), 1.56(m, 2H), 1.70(m, 2H), 4143-ethyl-6-methoxy-N-(1- 2.62(q, 2H), 3.83(s, 3H), 3.86(s, 3H), 4.01(m,1H), ethylpropyl)-5-(2- 4.10(d, 1H), 6.85(s, 1H), 6.87(d, 1H), 7.43(d,1H). difluoromethoxy-4- methoxyphenyl)pyrazin-2- amine 86E OCH₃ CF₃0.96(t, 6H), 1.27(t, 3H), 1.58(m, 2H), 1.70(m, 2H), 3983-ethyl-6-methoxy-N-(1- 2.63(q, 2H), 3.86(s, 3H), 3.87(s, 3H), 4.01(m,1H) ethylpropyl)-5-(2-methoxy- 4.13(m, 1H), 7.16(s, 1H), 7.27(d, 1H),7.47(d, 1H). 4-trifluoromethylphenyl) pyrazin-2-amine

Example 86f

[0323] 3-Ethyl-5-(2-methoxy-4-trifluoromethoxyphenyl)-[N-(1-ethyl)propyl] -6-methoxypyrazine-2-amine

[0324] A. (1-Ethyl-propyl)-(3-ethyl-pyrazin-2-yl)-amine. In a pressuretube, 2-chloro-3-ethyl-pyrazine (1.4 g, 10 mmol), Pd₂(dba)₃ (229 mg,0.25 mmol) and P(t-Bu)₃ (100 L, 0.4 mmol) were dissolved in toluene (15mL) and stirred at room temperature for 30 min. 1-Ethyl-propylamine(1.75 mL, 15 mmol) and KOt-Bu (1M in THF, 15 mmol, 15 mL) were added,and the dark solution was stirred at 55° C. (oil bath temperature) for90 min. The reaction mixture was allowed to reach room temperature,diluted with ethyl ether (100 mL) and washed with brine (3×100 mL).After drying with MgSO4, the solvents were removed under reducedpressure and a dark oil obtained. Flash chromatography (100% hexanes to20% ethyl acetate in hexanes) produced the desired product (710 mg,37%). H-1 NMR (CDCl₃, 300 MHz): 7.84 (1H, d, J=8.1 Hz), 7.68 (1H, d, J=9Hz), 4.15 (br, 1H), 4.05 (quint, 1H), 2.6 (2H, q, J=7.4 Hz), 1.4-1.6 (m,4H), 1.32 (t, 3H, J=7.4 Hz), 0.95 (t, 6H, J=7.4 Hz). MS: 194 (M+1,positive mode) and 192 (M−1, negative mode).

[0325] B. (5-Bromo-3-ethyl-pyrazin-2-yl)-(1-ethyl-propyl)-amine. Theproduct from step 1 (650 mg, 3.4 mmol) was dissolved in chloroform (20mL) and treated at room temperature with N-bromosuccinimide (600 mg, 3.5mmol). After 5 min the mixture was diluted with chloroform (100 mL) andthe organic solution washed with brine (3×100 mL), dried (MgSO₄),filtered, and the solvent removed under reduced pressure to produce5-bromo-3-ethyl-pyrazin-2-yl)-(1-ethyl-propyl)-amine (700 mg, 77%). H-1NMR (CDCl₃, 400 MHz): 7.94 (1H, s), 4.1 (br, 1H), 3.95 (quint, 1H), 2.60(2H, q, J=7.4 Hz), 1.4-1.6 (m, 4H), 1.32 (t, 3H, J=7.4 Hz), 0.95 (t, 6H,J=7.4 Hz). MS: 274.1 (M+1, positive mode) and 270.3 (M−1, negativemode).

[0326] C.[3-Ethyl-5-(2-methoxy-4trifluoromethoxy-phenyl)-pyrazin-2-yl]-(1-ethyl-propyl)-amine.

[0327] In a pressure tube, a mixture of the product from step 2 (700 mg,2.6 mmol), 2-methoxy-4-trifluoromethoxyboronic acid (1.0 g, 4.2 mmol)and Pd(PPh₃)₄ (100 mg) in toluene (10 mL), ethanol (0.5 mL) and aqueousK₂CO₃ (2M, 5 mL) was heated in oil bath at 80° C. for 16 h. The mixturewas diluted with ethyl acetate, and the organic fraction washed withNaOH (2M, 50 mL) and brine (3×50 mL), dried (MgSO4) filtered, and thesolvent removed under reduced pressure.

[0328] Flash chromatography of the residue (100% hexanes to 4% ethylacetate in hexanes) provided the desired product as an oil (850 mg,85%). H-1 NMR (CDCl₃, 300 MHz): 8.53 (1H, s), 7.91 (1H, is d, J=8.8 Hz),6.93 (1H, d, J=8.8 Hz), 6.80 (s, 1H), 4.18 (1H, d, J=8.2 Hz), 4.10(quint, 1H, J=5.8 Hz), 3.88 (3H, s), 2.6 (2H, q, J=7.4 Hz), 1.4-1.6 (m,4H), 1.37 (t, 3H, J=7.4 Hz), 0.95 (t, 6H, J=7.4 Hz). MS: 384.3 (M+1,positive mode) and 382.2 (M−1, negative mode).

[0329] D.[3-Ethyl-5-(2-methoxy-4-trifluoromethoxy-phenyl)-4-oxy-pyrazin-2-yl]-(1-ethyl-propyl)-amine.The aminopyrazine obtained in step 3 (370 mg, 0.97 mmol) was dissolvedin dichloromethane (15 mL) and treated with solid m-chloroperoxybenzoicacid (3 74 mg, 1.3 eq) at room temperature. After 3 h the reaction wasworked up by diluting with dichloromethane (50 mL) and washing with NaOH2M (25 mL) and brine (3×50 mL). The organic solution was dried (MgSO4),filtered and the solvent evaporated under reduced pressure. The residuewas purified by preparative thin layer chromatography, eluting with 30%ethyl acetate in hexanes), furnishing the desired product (55 mg, 14%).NMR (CDCl₃, 400 MHz) H-i: 7.86 (1H, s), 7.38 (1H, d, J=8.4 Hz), 6.89(1H, d, J=7.2 Hz), 6.81 (s, 1H), 4.21 (1H, d, J=8.0 Hz), 4.08 (quint,1H, J=6.0 Hz), 3.81 (3H, s), 2.9 (2H, q, J=7.6 Hz), 1.5-1.75 (m, 4H),1.23 (t, 3H, J=7.2 Hz), 0.96 (t, 6H, J=7.6 Hz). C-13: 158.96, 154.43,150.64, 142.56, 132.86, 132.47, 131.32, 119.15, 112.22, 104.58, 104.58,56.01, 53.35, 26.96, 17.89, 10.04, 8.86. F-19 NMR: −58.04 (s). (MS:400.3 (M+1, positive mode) and 398.3 (M−1, negative mode).

[0330] E.[6-Chloro-3-ethyl-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazin-2-yl]-(]-ethyl-propyl)-amine.The N-oxide from step 4 (40 mg, 0.1 mmol) was dissolved in OPCl₃ (1.5mL) and heated at 80° C. for 16 h. After cooling down to roomtemperature, the reaction mixture was diluted with ethyl ether (100 mL)and washed with NaOH (2M, 50 mL) and brine (3×50 mL), dried (MgSO4),filtered, and the solvent evaporated under reduced pressure to affordthe desired chloropyrazine (40 mg, 96%). NMR (CDCl₃, 400 MHz) H-1: 7.32(1H, d, J=8.4 Hz), 6.89 (1H, d, J=7.2 Hz), 6.80 (s, 1H), 4.26 (1H, d,J=8.4 Hz), 4.07 (quint, 1H, J=5.6 Hz), 3.82 (3H, s), 2.64 (2H, q, J=7.6Hz), 1.5-1.75 (m, 4H), 1.29 (t, 3H, J=7.6 Hz), 0.96 (t, 6H, J=7.2 Hz).C-13: 158.20, 150.91, 150.14, 143.80, 140.95, 134.30, 131.94, 126.07,112.44, 104.58, 55.78, 53.01, 26.81, 25.75, 10.80, 10.02. F-19 NMR:−58.03 (s). (MS: 418.2 (M+1, positive mode) and 416.2 (M−1, negativemode).

[0331] F.[3-Ethyl-6-methoxy-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazin-2-yl]-(1-ethyl-propyl)-amine.In a pressure tube, the chloropyrazine from step 5 (30 mg) was dissolvedin DMF (2 mL) and treated with sodium methoxide (100 mg) at 80° C. for120 h. The reaction mixture was diluted with ethyl ether (50 mL) andwashed with brine. The residue was purified 20 by preparative thin layerchromatography (15% ethyl acetate in hexanes to produce[3-ethyl-6-methoxy-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazin-2-yl]-(1-ethyl-propyl)-amine (10 mg, 33%), identical by tlc and NMR with anauthentic specimen.

Example 87

[0332]6-chloro-[N-(1-ethyl)propyl]-3-methoxy-5-(2,4-dichlorophenyl)pyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R,═OCH₃; R₂═—NHCH(CH₂CH₃)₂; R₃═Cl]

[0333] A. A solution in DMF (2 mL) of3-bromo-6-chloro-[N-(1-ethyl)propyl]pyrazine-2-amine (0.50 g; 1.8 mmol)obtained as a minor product in Example 75B is added into a solution ofsodium methoxide (freshly prepared from 90 mg of sodium metal inmethanol; 3.9 mmol) in DMF (3 mL). The mixture is stirred at roomtemperature overnight, then poured into aqueous ammonium chloridesolution and extracted twice with hexane-ethyl ether. Combined extractsare dried (sodium sulfate), filtered, concentrated in vacuo, andchromatographed on silica gel to give6-chloro-3-methoxy-[N-(1-ethyl)propyl]pyrazine-2-amine (410 mg).

[0334] B. The above material is brominated according to the sameprocedure used in Example 79 and further converted to the title compoundaccording to the same Suzuki coupling procedure used in Example 1C: ¹HNMR (CDCl₃, 400 MHz) δ 0.95 (t, 6H), 1.5-1.7 (m, 4H), 2.15 (s, 3H), 1o3.8 (s, 3H), 3.85 (s, 3H), 3.95 (s, 3H), 4.0 (m, 1H), 4.8 (br d, lH),6.55 (s, 1H), 6.55 (d, 1H), 7.3 (d, 1H).

Example 88

[0335]5-(2,4-dichlorophenyl)-[N-(1-ethyl)propyl]-3-methoxy-6-methylpyrazine-2-amine[Formula I: Ar=2,4-dichlorophenyl; R₁═OCH₃; R₂═—NHCH(CH₂CH₃)₂; R₃═CH₃]

[0336] A. 6-chloro-3-methoxy-[N-(1-ethyl)propyl]pyrazine-2-amineobtained in Example 87A is converted to 6-methyl derivative according tothe same procedure used in Example 85 and further brominated accordingto the same procedure used in Example 79.

[0337] B. The 5-bromopyrazine obtained as above is converted to thetitle compound according to the same procedure used in Example 1C: ¹HNMR (CDCl₃, 400 MHz) δ 0.95 (t, 6H), 1.5-1.7 (m, 4H), 2.15 (s, 3H), 3.9(s, 3H), 4.05 (m, 1H), 4.8 (br d, 1H), 7.3 (s, 2H), 7.45 (s, 1H); MS(CI) 356.

[0338] Examples 89-90 may be prepared according to the general proceduredescribed in Example 88.

Example 89

[0339][N-(1-ethyl)propyl]-3-methoxy-5-(2,4-dimethoxyphenyl)-6-methylpyrazine-2-amine[Formula I: Ar=2,4-dimethoxyphenyl; R₁═OCH₃; R₂═—NHCH(CH₂CH₃)₂; R₃═CH₃]

[0340]¹H NMR (CDCl₃, 400 MHz): δ 0.95 (t, 6H), 1.5-1.7 (m, 4H), 2.15 (s,3H), 3.8 (s, 3H), 3.85 (s, 3H), 3.95 (s, 3H), 4.0 (m, 1H), 4.7 (br d,1H), 6.5 (s, 1H), 6.55 (d, 1H), 7.2 (d, 1H); MS (CI) 346.

Example 90

[0341][N-(1-ethyl)propyl]-3-methoxy-5-(4-methoxy-2-methylphenyl)-6-methylpyrazine-2-amine[Formula I: Ar=2-methyl-4-methoxyphenyl; R₁═OCH₃; R₂═—NHCH(CH₂CH₃)₂;R₃═CH₃]

[0342]¹H NMR (CDCl₃, 400 MHz): δ 0.95 (t, 6H), 1.5-1.7 (m, 4H), 2.15 (s,3H), 2.2 (s, 3H), 3.8 (s, 3H), 3.9 (s, 3H), 4.0 (m, 1H), 4.7 (br d, 1H),6.75 (d, 1H), 6.8 (s, 1H), 7.15 (d, 1H); MS (CI) 330.

Example 91

[0343]{4-[6-Ethyl-5-(ethylpropoxy)-3-methoxypyrazin-2-yl]-3-methoxyphenoxy}trifluoromethane

[0344] A. To a stirred solution of 2,6-dichloropyrazine (25 g, 0.167mol) and ethanol (120 mL) in a sealed tube is added 4-methoxybenzylamine(68.6 g, 0.5 mol). The mixture is heated to 115 C for 12 h and cooled.The white solid is removed by filtration and the filtrate evaporated.The residue is dissolved in ethyl acetate and washed successively with2M sodium hydroxide, water and aqueous sodium chloride. The organics aredried (magnesium sulfate), filtered, and evaporated to give(6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine (35.5 g), a whitesolid.

[0345] B. To a stirred solution of(6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine (5.0 g, 20.0 mmol)in DMF (30 mL) is added sodium methoxide (7.50 g, 125.0 mmol). Themixture is heated at reflux for 12 h, cooled and partitioned betweenethyl acetate (100 mL) and water (100 mL). The layers are separated andthe organic layer washed with water (3×100 mL). The combined extractsare dried (magnesium sulfate), filtered, and evaporated to give[(4-methoxyphenyl)methyl](6-methoxypyrain-2-yl)amine (4.65 g), a yellowsolid.

[0346] C. A solution of[(4-methoxyphenyl)methyl](6-methoxypyrain-2-yl)amine (2.45 g, 10.0 mmol)in chloroform (50 mL) is cooled to 0 C and N-bromosuccinimide (1.8 g,10.0 mmol) is added in portions. After the addition, the mixture isfurther stirred for 1 h while being allowed to warm to room temperature.The mixture is washed with saturated aqueous sodium bicarbonate, aqueoussodium chloride, dried (magnesium sulfate), filtered and evaporated. Theresidue is purified by flash chromatography, eluting with 20% ether inhexanes to give(5-bromo-6-methoxypyrazin-2-yl)[(4-methoxyphenyl)methyl]amine (1.1 g).

[0347] D. To a stirred solution of(5-bromo-6-methoxypyrazin-2-yl)[(4-methoxyphenyl)methyl]amine (0.80 g,2.50 mmol) and 2-methoxy-4-trifluoromethoxybenzeneboronic acid (1.75 g,7.5 mmol) in toluene (25 mL) is addedtetrakis(triphenylphosphine)palladium(0) (100 mg) and potassiumcarbonate (2.0 M, 2.0 mL). The mixture is heated to 85 C for 8 h, cooledto room temperature, diluted with 2.0 M sodium hydroxide and extractedtwice with 1:1 hexane-ethyl ether. The combined extracts are dried(sodium sulfate), filtered and concentrated. The residue is purified byflash chromatography, eluting with 60% hexanes in ether to give{6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine (967 mg).

[0348] E. A solution of {6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine (870 mg, 2.0 mmol) in chloroform (10 mL)is cooled to 0 C and N-bromosuccinimide (356 mg, 2.0 mmol) is added inportions. After the addition, the mixture is further stirred for 1 hwhile being allowed to warm to room temperature. The mixture is washedwith saturated aqueous sodium bicarbonate, aqueous sodium chloride,dried (magnesium sulfate), filtered, and evaporated to give{3-bromo-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine (920 mg), a yellow solid.

[0349] F. To a stirred solution of{3-bromo-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine (514 mg, 1.0 mmol) and ethylboronic acid(219 mg, 3.0 mmol) in toluene (8 mL) is addedtetrakis(triphenylphosphine)palladium(0) (50 mg) and potassium carbonate(2.0 M, 1.0 mL). The mixture is heated to 85 C for 8 h, cooled to roomtemperature, diluted with 2.0 M sodium hydroxide and extracted twicewith 1:1 hexane- ethyl ether. The combined extracts are dried (sodiumsulfate), filtered and concentrated. The residue is purified by flashchromatography, eluting with 20% ether in hexanes to give{3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine (430 mg).

[0350] G. To{3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine(115 mg, 0.25 mmol) in methanol (3 mL) under a nitrogen 2 5 atmosphereis added 1M hydrochloric acid in ether (2 mL) and 10% palladium oncarbon (40 mg). The mixture is then hydrogenated at 1 ATM for 18 h,filtered through Celite and evaporated to give3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-ylamine(80 mg).

[0351] H. To a stirred solution of3-ethyl-6-methoxy-5-[2-methoxy-4-trifluoromethoxy)phenyl]pyrazin-2-ylamine(86 mg, 0.25 mmol) in 48% hydrogen bromide (0.3 mL) at 0 C is added asolution of sodium nitrite (21 mg, 0.3 mmol) in water (1 mL). After 1.5h copper bromide (43 mg, 0.3 mmol) is added and the mixture heated to 70C for 1 h. The mixture is cooled to room temperature and extracted withether. The extracts are dried (sodium sulfate), filtered andconcentrated to give[4-(5-bromo-6-ethyl-3-methoxypyrazin-2-yl)-3-methoxyphenoxy]trifluoromethane(76 mg).

[0352] I. To a stirred solution of 3-pentanol (88 mg, 1 mmol) in THF (1mL) is added 60% sodium hydride (12 mg, 0.3 mmol) and after 0.5 h[4-(5-bromo-6-ethyl-3-methoxypyrazin-2-yl)-3-methoxyphenoxy]trifluoromethane(41 mg, 0.1 mmol) is added. The mixture is heated to 50 C for 12 h,cooled and partitioned between ethyl acetate and water. The organiclayer is washed with water, brine, dried (sodium sulfate), filtered andconcentrated. The residue is purified by preparative TLC eluting with50% ether in hexanes to give{4-[6-Ethyl-5-(ethylpropoxy)-3-methoxypyrazin-2-yl]-3-methoxyphenoxy}trifluoromethane,a colorless oil (19 mg). NMR (CDCL₃, 400 MHz) 0.98 (t, 6H), 1.22 (t,3H), 1.78 (m, 4H) 2.80 (q, 2H), 3.80 (s, 3H), 3.88 (s, 3H), 5.05(quintet, 1H), 6.8 (s, 1H), 6.90 (d, 1H), 7.37 (d, 1H); MS 345 (M+1).

[0353] Additional compounds prepared and assayed by the methodsdescribed herein are shown in Table VII. TABLE VII Formula I

Cpnd Synthetic IMR32 No. Ar R₁ R₂ R₃ Method Binding Name 91a 2,4,6- CH₃3- CH₃ Example 40 nM 3,6-dimethyl-N-(1- trichlorophenyl pentyl Iethylpropyl)-5-(2,4,6- amino trimethylphenyl)pyrazin- 2-amine 91b 2,4-Br 3- Cl Example 28 nM 3-bromo-6-chloro-N-(1- dichlorophenyl pentyl Iethylpropyl)-5-(2,4- amino dichlorophenyl)pyrazin-2- amine

Example 92

[0354] Synthesis of[3-ethyl-5-(2-methoxy-4-trifluoromethoxy-phenyl)-6-methylsulfanyl-pyrazin-2-yl]-(1-ethyl-propyl)-amine.

[0355] In a pressure tube equipped with Teflon 0-ring were combined[6-chloro-3-ethyl-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazin-2-yl]-(1-ethyl-propyl)-amine (100 mg) obtained in step E of Example 86e, NaSMe(200 mg), THF (5 mL) and DMF (3 mL). The mixture was heated at 80° C.(oil bath temperature) for 72 h. The crude mixture was diluted withethyl acetate (40 mL) and water (40 mL), and the organic phase washedwith brine (3×100 mL). After drying (MgSO4), filtration and eliminationof solvents at reduced pressure, the title compound was isolated as aclear oil by preparative thin layer chromatography (10% EtOAc inhexanes). Yield was 50 mg (49%). NMR (CDCl₃, 400 MHz) H-1: 7.32 (lH, d,J=8.4 Hz), 6.88 (1H, m), 6.78 (s, 1H), 4.18 (1H, d), 4.07 (m, 1H), 3.78(3H, s), 2.64 (2H, q), 2,24 (s, 3H), 1.5-1.75 (m, 4H), 1.25 (t, 3H),0.96 (t, 6H). MS: 430.2 (M+1, positive mode) and 428.4 (M−1, negativemode).

Example 93

[0356] 2-sec-butylsulfanyl-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine

[0357] NaH (60 mg, 1.5 mmol. 60% in mineral oil) was added to a solutionof butane-2-thiol (170 μL, 1.5 mmol) in THF (5 mL). After 10 minutes,2-chloro-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine (100 mg, 0.33mmol) obtained as in Example 45, steps A-C, in THF (1 mL) was addeddropwise, and the mixture heated at 80° C. (oil bath temperature) for 16h. After extractive work-up, preparative thin layer chromatography(hexanes) furnished the title compound as a clear oil (60 mg, 51%). NMR(CDCl₃, 400 MHz) H-1: 7.19 (1H, d, J=8.4 Hz), 6.58 (1H, dd, J=2.4, 8.4Hz), 6.60 (s, 1H, J=2.4 Hz), 3.99 (sext, 1H, J=6.8 Hz), 3.85 (3H, s),3.75 (3H, s), 2.81 (2H, q, J=7.4 Hz), 2.58 (2H, br q, J=6.8 Hz), 1.6-1.9(m, 4H), 1.44 (3H, d, J=6.4 Hz), 1.28 (t, 3H, J=7.6 Hz), 1.19 (3H, t,J=7.6 Hz), 1.06 (t, 3H, J=7.2 Hz). C-13: 161.10, 157.86, 153.49, 151.79,151.67, 144.47, 131.68, 121.18, 104.78, 98,60, 55.44, 55.33, 40.87,29.65, 27.54, 27.08, 20.56, 12.43, 12.09, 11.51. MS: 414.2 (M+1,positive mode) and 412.2 (M−1, negative mode).

Example 93a

[0358] 2-Sec-butylsulfanyl-5-(2,4-dichloro-phenyl)-3,6-diethyl-pyrazine.

[0359] By a similar procedure, but starting from2-chloro-5-(2,4-dichloro-phenyl)-3,6-diethyl-pyrazine obtained as inExample 49 steps A-C, was obtained2-sec-butylsulfanyl-5-(2,4-dichloro-phenyl)-3,6-diethyl-pyrazine. NMR(CDCl₃, 400 MHz) H-1: 7.19 (1H, d, J=2.0 Hz), 7.26 (1H, dd, J=2.0, 8.0Hz), 7.18 (1H, d, J=8.0 Hz), 3.92 (1H, sext, J=6.8 Hz), 2.72 (2H, q,J=7.6 Hz), 2.58 (2H, br), 1.6-1.8 (m, 4H), 1.36 (3H, d, J=6.8 Hz), 1.20(t, 3H, J=7.6 Hz), 1.12 (3H, t, J=7.6 Hz), 0.98 (t, 3H, J=7.6 Hz). C-13:153.93, 152.40, 152.00, 143.69, 136.46, 134.73, 134.40, 131.94, 129.48,127.24, 41.01, 29.56, 27.40, 27.10, 20.45, 12.48, 11.86, 11.51. MS:369.2 (M+1, positive mode).

Example 93b

[0360]2-Sec-butylsulfanyl-3-ethyl-6-methoxy-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazine.

[0361] By a similar procedure, but starting from2-bromo-3-ethyl-6-methoxy-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazineobtained as in Example 49 steps A-C, was obtained2-sec-butylsulfanyl-3-ethyl-6-methoxy-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazine.NMR (CDCl₃, 400 MHz) H-1: 7.37 (1H, d, J=8.4 Hz), 6.91 (1H, m), 6.80(1H, s), 3.94 (3H, s), 3.89 (1H, m), 3.79 (3H, s), 2.78 (2H, q, J=7.6Hz), 1.7-1.9 (m, 4H), 1.46 (3H, d, J=6.8 Hz), 1.27 (t, 3H, J=7.2 Hz),1.07 (3H, t, J=7.2 Hz). C-13: 158.43, 155.85, 150.32, 149.90, 146.33,135.34, 133.73, 131.85, 124.81, 112.66, 104.85, 55.93, 53.57, 41.47,29.61, 26.83, 20.61, 12.30, 11.54. F-19 NMR: −58.04 (s). MS: 417.2 (M+1,positive mode).

Example 94

[0362]1-[3,6-diethyl-5-(2-methylbutyl)pyrazin-2-yl]-2,4-dimethoxybenzene

[0363] To a solution of 2-methyl-1-butene (210 mg, 3.0 mmol) in THF isadded a solution of 9-BBN (9-borabicyclo[3.3.1]nonane) in THF (0.5 M,6.0 mL, 3.0 mmol). The mixture is heated at reflux, under a nitrogenatmosphere for 12 h and cooled. To the solution is added1-(5-bromo-3,6-diethylpyrazin-2-yl)-2,4-dimethoxybenzene (664 mg, 2.0mmol), obtained as in Example 49 steps A-C, tetrakis(triphenylphosphine)palladium(0) (50 mg) and sodium hydroxide (3.0 M, 3.0 mL, 3.0 mmol). Themixture is heated at 50 C for 12 h and cooled. 30% Hydrogen peroxide (1mL) is added, the solution stirred for 1 h and the reaction mixtureextracted with ether. The combined extracts are dried (sodium sulfate),filtered and concentrated. The residue is purified by flashchromatography, eluting with 40% ether in hexanes to give1-[3,6-diethyl-5-(2-methylbutyl)pyrazin-2-yl]-2,4-dimethoxybenzene (393mg).

Example 95

[0364]2-(2-methoxy-5-triflurormethoxyphenyl)-3-ethyl-6-methylamino-5-(1-ethylpropoxy)-pyrazine

[0365] (6-Chloropyrazin-2-yl)[(4-methoxyphenyl)methyl] amine is preparedby Step A of Example 91.

[0366] A. A solution of6-(Chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine in chloroform (4mL/mmol NBS) is cooled to 0° C. and N-bromosuccinimide (1.05 eq) isadded in portions while stirring the reaction mixture. After completeaddition, the mixture is further stirred for 1 hour while being allowedto warm to room temperature. The mixture is then diluted withdichloromethane, washed with saturated NaHCO₃, water, brine and thendried and filtered. The filtrate is concentrated and purified bychromatography on silica gel to give(5-bromo-6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl] amine.

[0367] B. In a pressure tube, a mixture of the product from step A (1equivalent), 2-methoxy-5-trifluoromethoxyphenylboronic acid (1.6equivalents) and Pd(PPh₃)₄ (0.04 equivalents) in toluene (4 ml/mmol ofproduct from step A), ethanol (0.2 ml/ mmol of product from step A) andaqueous K₂CO₃ (2M, 2 ml/mmol of product from step A) is heated to 80° C.for 16 h. The mixture was diluted with ethyl acetate, and the organicfraction washed with NaOH (2M, 20 mL/mmol of product from step A) andbrine (3×20 ml/mmol of product from step A), then dried (MgSO₄),filtered and the solvent removed under reduced pressure. Chromatographyof the residue provided(3-(2-methoxy-5-trifluoromethoxyphenyl)-6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]amine.

[0368] C.(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin-2-yl)[(4-methoxyphenyl)methyl]aminecan be prepared by the method of Example 1, step A by substituting(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl]aminefor 2-chloro-3,6-dimethylpyrazine.

[0369] D.(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin-2-yl)amine can beprepared by the hydrogentation method of Example 91, step G bysubstituting(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin-2-yl)[(4-methoxyphenyl)methyl]aminefor{3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine.

[0370] E. 2-Bromo-5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazinecan be prepared 20Q by the halogenation method of Example 91, step H bysubstituting(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin-2-yl)amine for{3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}amine.

[0371] F.2-(3-Pentoxy)-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazinecan be 2 5 prepared by the method of Example 91, step I by substituting2-bromo-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin-2-yl)[(4-methoxyphenyl)methyl]aminefor [4-(5-bromo-6-ethyl-3-methoxypyrazin-2-yl)-3-methoxyphenoxy]trifluoromethane.

[0372] G.2-(3-Pentoxy)-3-bromo-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazinecan be prepared by the method of step A of the present Example bysubstituting2-(3-Pentoxy)-3-bromo-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazinefor (6-chloropyrazin-2-yl)[(4-methoxyphenyl)methyl] amine.

[0373] H. To a mixture of2-(3-Pentoxy)-3-bromo-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazine(1 equivalent), tris(dibenzylideneacetone)dipalladium(0) (2 mol %), and1,1′-binaphthyl-2,2′-di(diphenylphosphine) (BINAP) (6 mol %) inethyleneglycol dimethyl ether (2.4 mL/mmol substrate) under nitrogen isadded methylamine (1.2 equivalents) followed by sodium tert-butoxide(1.5 equivalents). The mixture is stirred at 70-80° C. for about 2.5hours, diluted with aqueous ammonium chloride, and extracted with 1:1hexane-diethyl ether. The combined extracts are dried (sodium sulfate),filtered, concentrated and then purified by chromatography on silica gelto afford2-(3-Pentoxy)-3-(N-methylamino)-(5-(2-methoxy-5-trifluoromethoxyphenyl)-6-ethylpyrazin

Example 96

[0374] Assay for CRF Receptor Binding Activity

[0375] As discussed above, the following assay is defined herein as astandard in vitro CRF receptor binding assay.

[0376] The pharmaceutical utility of compounds of this invention isindicated by the following assay for CRF1 receptor activity. The CRFreceptor binding is performed using a modified version of the assaydescribed by Grigoriadis and De Souza (Methods in Neurosciences, Vol. 5,1991). IMR-32 human neuroblastoma cells, a cell-line that naturallyexpresses the CRF1 receptor, are grown to confluency in DMEM containingFBS.

[0377] To prepare receptor containing membranes cells are homogenized inwash buffer (50 mM Tris HCl, 10 mM MgCl₂, 2 mM EGTA, pH 7.4) andcentrifuged at 48,000×g for 10 minutes at 4° C. The pellet isre-suspended in wash buffer and the homogenization and centrifugationsteps are performed two additional times.

[0378] Membrane pellets containing CRF receptors are re-suspended in 50mM Tris buffer pH 7.7 containing 10 mM MgCl₂ and 2 mM EDTA andcentrifuged for 10 minutes at 48000 g. Membranes are washed again andbrought to a final concentration of 1500 mg/ml in binding buffer (Trisbuffer above with 0.1% BSA, 15 mM bacitracin and 0.01 mg/ml aprotinin.).For the binding assay, 100 ml of the membrane preparation are added to96 well microtube plates containing 100 ml of ¹²⁵I-CRF (SA 2200 Ci/mmol,final concentration of 100 pM) and 50 ml of test compound. Binding iscarried out at room temperature for 2 hours. Plates are then harvestedon a Brandel 96 well cell harvester and filters are counted for gammaemissions on a Wallac 1205 Betaplate liquid scintillation counter. Nonspecific binding is defined by 1 mM cold CRF. IC₅₀ values are calculatedwith the non-linear curve fitting program RS/1 (BBN Software ProductsCorp., Cambridge, Mass.). The binding affinity for the compounds ofFormula I expressed as IC₅₀ value, generally ranges from about 0.5nanomolar to about 10 micromolar. Preferred compounds of Formula Iexhibit IC₅₀ values of less than or equal to 1.5 micromolar, morepreferred compounds of Formula I exhibit IC₅₀ values of less than 500nanomolar, still more preferred compounds of Formula I exhibit IC₅₀values of less than 100 nanomolar, and most preferred compound ofFormula I exhibit IC₅₀ values of less than 10 nanomolar. The compoundsshown in Examples 1-95 and Examples 100-396 have been tested in thisassay and found to exhibit IC₅₀ values of less than or equal to 1.5micromolar.

Example 97

[0379] Preparation of radiolabeled probe compounds of the invention

[0380] The compounds of the invention are prepared as radiolabeledprobes by carrying out their synthesis using precursors comprising atleast one atom that is a radioisotope. The radioisotope is preferablyselected from of at least one of carbon (preferably ¹⁴C), hydrogen(preferably ³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I).Such radiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

[0381] Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound of theinvention as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

Example 98

[0382] Receptor autoradiography

[0383] Receptor autoradiography (receptor mapping) is carried out invitro as described by Kuhar in sections 8.1.1 to 8.1.9 of CurrentProtocols in Pharmacology (1998) John Wiley & Sons, New York, usingradiolabeled compounds of the invention prepared as described in thepreceding Example.

Example 99

[0384] Additional Aspects of Preferred Compounds of the Invention

[0385] The most preferred compounds of the invention are suitable forpharmaceutical use in treating human patients. Accordingly, suchpreferred compounds are non-toxic. They do not exhibit single ormultiple dose acute or long-term toxicity, mutagenicity (e.g., asdetermined in a bacterial reverse mutation assay such as an Ames test),teratogenicity, tumorogenicity, or the like, and rarely trigger adverseeffects (side effects) when administered at therapeutically effectivedosages.

[0386] Preferably, administration of such preferred compounds of theinvention at certain doses (e.g., doses yielding therapeuticallyeffective in vivo concentrations or preferably doses of 10, 50, 100,150, or 200 mg/kg—preferably 150 mg/kg—administered parenterally orprefrerably orally) does not result in prolongation of heart QTintervals (i.e., as determined by electrocardiography, e.g., in guineapigs, minipigs or dogs). When administered daily for 5 or preferably tendays, such doses of such preferred compounds also do not cause liverenlargement resulting in an increase of liver to body weight ratio ofmore than 100%, preferably not more than 75% and more preferably notmore than 50% over matched controls in laboratory rodents (e.g., mice orrats). In another aspect such doses of such preferred compounds alsopreferably do not cause liver enlargement resulting in an increase ofliver to body weight ratio of more than 50%, preferably preferably notmore than 25%, and more preferably not more than 10% over matcheduntreated controls in dogs or other non-rodent animals.

[0387] In yet another aspect such doses of such preferred compounds alsopreferably do not promote the release of liver enzymes (e.g., ALT, LDH,or AST) from hepatocytes in vivo. Preferably such doses do not elevatesuch enzymes by more than 100%, preferably not by more than 75% and morepreferably not by more than 50% over matched untreated controls inlaboratory rodents. Similarly, concentrations (in culture media or othersuch solutions that are contacted and incubated with cells in vitro)equivalent to two, fold, preferably five-fold, and most preferablyten-fold the minimum in vivo therapeutic concentration do not causerelease of any of such liver enzymes from hepatocytes in vitro.

[0388] Because side effects are often due to undesirable receptoractivation or antagonism, preferred compounds of the invention exerttheir receptor-modulatory effects with high selectivity. This means thatthey do not bind to certain other receptors (i.e., other than CRFreceptors) with high affinity, but rather only bind to, activate, orinhibit the activity of such other receptors with affinity constants ofgreater than 100 nanomolar, preferably greater than 1 micromolar, morepreferably greater than 10 micromolar and most preferably greater than100 micromolar. Such receptors preferably are selected from the groupincluding ion channel receptors, including sodium ion channel receptors,neurotransmitter receptors such as alpha- and beta-adrenergic receptors,muscarinic receptors (particularly m1, m2, and m3 receptors), dopaminereceptors, and metabotropic glutamate receptors; and also includehistamine receptors and cytokine receptors, e.g., interleukin receptors,particularly IL-8 receptors. The group of other receptors to whichpreferred compounds do not bind with high affinity also includesGABA_(A) receptors, bioactive peptide receptors (including NPY and VIPreceptors), neurokinin receptors, bradykinin receptors (e.g., BK1receptors and BK2 receptors), and hormone receptors (includingthyrotropin releasing hormone receptors and melanocyte-concentratinghormone receptors).

Example 99a

[0389] Absence of Sodium Ion Channel Activity

[0390] Preferred compounds of the invention do not exhibit activity asSodium ion channel blockers. Sodium channel activity may be measured astandard in vitro sodium channel binding assays such as the assay givenby Brown et al. (J. Neurosci. (1986) 265:17995-18004). Preferredcompounds of the invention exhibit less than 15 percent inhibition, andmore preferably less than 10 percent inhibition, of sodium channelspecific ligand binding when present at a concentration of 4 μM. Thesodium ion channel specific ligand used may be labeled batrachotoxinin,tetrodotoxin, or saxitoxin. Such assays, including the assay of Brownreferred to above, are performed as a commercial service by CEREP, INC.,Redmond, Wash.

[0391] Alternatively, sodium ion channel activity may be measured invivo in an assay of anti-epileptic activity. Anti-epileptic activity ofcompounds may be measured by the ability of the compounds to inhibithind limb extension in the supra maximal electro shock model. Male HanWistar rats (150-200 mg) are dosed i.p. with a suspension of 1 to 20 mgof test compound in 0.25% methylcellulose 2 hr. prior to test. A visualobservation is carried out just prior to testing for the presence ofataxia. Using auricular electrodes a current of 200 mA, duration 200millisec, is applied and the presence or absence of hind limb extensionis noted. Preferred compounds of the invention do not exhibitsignificant anti-epileptic activity at the p<0.1 level of significanceor more preferably at the p<0.05 level of significance as measured usinga standard parametric assay of statistical significance such as astudent's T test.

Example 99b

[0392] Optimal in vitro half-life

[0393] Compound half-life values (t_(½) values) may be determined viathe following standard liver microsomal half-life assay. Livermicrosomes obtained from pooled liver samples and prepared so that theP-450 enzyme content is approximately 0.5 nmol/ mg protein. Reactionsare preformed in a 5 ml well deep-well plate as follows:

[0394] Phosphate buffer: 19 mL 0.1 M NaH₂PO₄, 81 mL 0.1 Na₂HPO₄, pH 7.4with H₃PO₄.

[0395] CoFactor Mixture: 16.2 mg NADP, 45.4 mg Glucose-6-phosphate in 4mL 100 mM MgCl₂.

[0396] Glucose-6-phosphate dehydrogenase: 214.3 ul glucose-6-phosphatedehydrogenase, 1285.7 ul distilled water

[0397] Starting Reaction Mixture: 3 mL CoFactor Mixture, 1.2 mLGlucose-6-phosphate dehydrogenase 6 identical samples wells eachcontaining 25 ul microsomes, 5 ul of test compound (from a 100 uMstock), and 399 ul 0.1 M phosphate buffer, pH 7.4, are prepared. Aseventh well containing 25 ul microsomes, 399 ul 0.1 M phosphate buffer,pH 7.4, and 5 ul (from a 100 uM stock) of a compound, e.g. DIAZEPAM,CLOZEPINE, with known metabolic properties is used as a positivecontrol. Reactions are preincubated at 39° C. for 10 minutes. 71 ulStarting Reaction Mixture is added to 5 of the 6 reaction wells and tothe positive control well, 71 ul 100 mM MgCl₂ is added to the sixthreaction well, which is used as a negative control. At each time point(0, 1, 3, 5, and 10 minutes) 75 ul reaction is pipetted into a 96-welldeep-well plate reaction well containing 75 ul ice-cold acetonitrile.Samples are vortexed and centrifuged 10 minutes at 6000 rpm (Sorval T6000D rotor). Supernatant, 75 ul from each reaction well, is transferredto a 96-well plate containing 150 ul internal standard per well. Theremaining test compound is quantitated via LCMS and Compoundconcentration vs time is plotted and commercially available statisticalsoftware is used to extrapolate to the tl,₂ value of the test compound.

[0398] Preferred compounds of the invention exhibit in vitro tl/₂ valuesof greater than 10 minutes and less than 4 hours. Most preferredcompounds of the invention exhibit in vitro t_(½) values of between 30minutes and 1 hour in human liver microsomes.

Example 99c

[0399] MDCK Toxicity

[0400] Toxicity of a test compound may be assessed by measuring theeffect of the compound on ATP production by MDCK cells.

[0401] MDCK cells, product no. CCL-34, are purchased from ATCC,Manassas, Va. and maintained in sterile conditions by the methodsdescribed in the supplier's production information sheet. The PACKARDBIOSCIENCE, (Groningen, The Netherlands) ATP-LITE-M Luminescent ATPdecection kit, product no. 6016941, may be used to monitor ATPproduction in MDCK cells.

[0402] Prior to assay 1 ul of test compound or control sample ispipetted into PACKARD (Meriden, Conn.) clear bottom 96-well plates. Testcompounds and control samples are diluted in DMSO to give finalconcentration in the assay of 10 micromolar, 100 micromolar, or 200micromolar. Control samples are drug compounds having known toxicityproperties.

[0403] Confluent MDCK cells are trypsinized, harvested, and diluted to aconcentration of 0.1×10⁶ cells/ ml with warm ATCC Eagle's MinimumEssential Medium (catalog # 30-2003). Warm Eagle's MEM without cells(100ul) is pipetted in five wells a 96-well plate. These wells are usedto determine the standard curve. Cells in Eagle's MEM (100ul or 10,000cells) are pipetted into the remaining wells of the 96-well plates. Allsamples are incubated at 37° C. under carbogen (95% O₂, 5% CO₂) for 2hours with constant shaking. After incubation 50 ul mammalian cell lysissolution is added to well of the 96-well plates, wells are covered withPackard topseal stickers, and plates are shaken at approximately 700 rpmon a microtiter shaker for 2 minutes.

[0404] During the incubation, Packard ATP Lite-M reagents are allowed toequilibrate to room temperature. Once equilibrated the lyophilizedsubstrate solution in reconstituted in 5.5 mls of substrate buffersolution (from kit). Lyophilized ATP standard solution is reconstitutedin deionized water to give a 10 mM stock. Standard (10 ul), diluted sothat a 10 ul aliquot yields a final concentration of 200 nM, 100 nM, 50nM, 25 nM, or 12.5 nM is added to each of the five standard curve wells,which do not contain cells.

[0405] Substrate solution (50 ul) is added to all wells. Wells arecovered with Packard topseal stickers, and plates are shaken atapproximately 700 rpm on a microtiter shaker for 2 minutes. A whitePackard sticker is attached to the bottom of each plates and samples aredark adapted by wrapping plates in foil and placing in the dark for 10minutes. Luminescence is then quantitated at 22° C. using a luminescencecounter, e.g. Packard TopCount Microplate Scintillation and LuminescenseCounter or Tecan Spectrafluor plus.

[0406] Luminscence values at each concentration are compared to thevalues computed from the standard curve for that concentration.Preferred test compounds exhibit luminescence values 80% or more of thestandard, or preferably 90% or more of the standard, when 10 micromolarconcentration of the test compound is used. When a 100 micromolarconcentraion of the test compound is used, preferred test compoundsexhibit luminescence values 50% or more of the standard, or morepreferably 80% or more of the standard.

Examples 100-396

[0407] Additional compounds of the invention prepared by the methodsdescribed for compounds shown in Examples 1-95 are shown in TABLE VIIIEX# STRUCTURE IUPAC Name 100

5-(2,4-dimethoxyphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 101

6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethyl)phenyl]pyrazin-2- amine 102

3-bromo-5-(2,4-dimethoxyphenyl)-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 103

6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-[4-methoxy-2-(trifluoromethoxy)phenyl]pyrazin- 2-amine 104

5-[4-bromo-2-(trifluoromethoxy)phenyl]-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 105

6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin- 2-amine 106

2,5-diethyl-3-(1-ethylpropoxy)-6-[4-methoxy-2-(trifluoromethoxy)phenyl]pyrazine 107

5-(2,4-dimethoxyphenyl)-3,6-diethyl-N-(1-ethylpropyl)-N-propylpyrazin-2-amine 108

3-ethyl-N-(1-ethylpropyl)-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin- 2-amine 109

5-(2,4-dimethoxyphenyl)-N-(1-ethylpropyl)- 3,6-dimethoxypyrazin-2-amine110

5-(5-chloro-4-methoxy-2-methylphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2- amine 111

5-(5-chloro-4-methoxy-2-methylphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 112

5-(4-chloro-2-methylphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 113

5-[2-chloro-4-(trifluoromethyl)phenyl]-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 114

5-(5-bromo-2,4-dimethoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 115

5-(2,4-dichloro-6-methylphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 116

3,6-diethyl-N-(1-ethylpropyl)-5-(2,3,4- trimethoxyphenyl)pyrazin-2-amine117

5-[2-chloro-4-(trifluoromethyl)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2- amine 118

5-[4-(difluoromethoxy)-2-methoxyphenyl]-3,6diethyl-N-(1-ethylpropyl)pyrazin-2-amine 119

2-[2-chloro-4-(trifluoromethyl)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine 120

2-[2,4-bis(trifluoromethyl)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine 121

5-(2,4-difluorophenyl)-3,6-diethyl-N-(1- ethylpropyl)pyrazin-2-amine 122

3,6-diethyl-N-(1-ethylpropyl)-5-(1- naphthyl)pyrazin-2-amine 123

3,6-diethyl-N-(1-ethylpropyl)-5-(2- naphthyl)pyrazin-2-amine 124

6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-[4-methoxy-2-(trifluoromethyl)phenyl]pyrazin-2- amine 125

5-(2,4-dimethoxypheny1)-3,6-diethyl-N-(1-ethylpropyl)-N-methylpyrazin-2-amine 126

5-[4-chloro-2-(trifluoromethyl)phenyl]-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 127

5-[2-chloro-4-(trifluoromethoxy)phenyl]-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 128

2-(2,4-dichlorophenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 129

2-(2,4-dichlorophenyl)-3,6-diethyl-5-(1- ethylbutoxy)pyrazine 130

2-(2,4-dichlorophenyl)-3,6-diethyl-5-(1-ethyl- 2-methylpropoxy)pyrazine131

3,6-diethyl-N-(1-ethylpropyl)-5-[2-methoxy-6-(trifluoromethoxy)phenyl]pyrazin-2-amine 132

2-(2,4-dichlorophenyl)-3,6-diethyl-5-(1- phenylpropoxy)pyrazine 133

2-(2,4-dichlorophenyl)-3,6-diethyl-5-[(1- ethylpentyl)oxy]pyrazine 134

5-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 135

5-(2-chloro-4-methoxyphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 136

5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 137

3,6-diethyl-N-(1-ethylpropyl)-5-[4-fluoro-2-(trifluoromethyl)phenyl]pyrazin-2-amine 138

5-[2,4-bis(trifluoromethyl)phenyl]-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 139

5-(2,6-dichloro-4-methoxyphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 140

5-[2-chloro-4-(trifluoromethyl)phenyl]-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2- amine 141

2-[cyclopropyl(phenyl)methoxy]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine 142

5-[2-chloro-4-(trifluoromethoxy)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2- amine 143

3,6-diethyl-N-(1-ethylpropyl)-5-(3-methyl-1,1′biphenyl-4-yl)pyrazin-2-amine144

2-[2-chloro-4-(trifluoromethoxy)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine 145

3,6-diethyl-N-(1-ethylpropyl)-5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-amine 146

6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2- amine 147

5-[2,4-bis(trifluoromethyl)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 148

5-(2-chloro-4-ethoxyphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 149

2-(2,4-dimethoxyphenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 150

2-sec-butoxy-5-(2,4-dichlorophenyl)-3,6- diethylpyrazine 151

2-(2,4-dichlorophenyl)-3,6-diethyl-5-(1- methylbutoxy)pyrazine 152

2-(2,4-dichlorophenyl)-5-(1,2- dimethylpropoxy)-3,6-diethylpyrazine 153

2-(2,4-dichlorophenyl)-3,6-diethyl-5-(1- propylbutoxy)pyrazine 154

2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)- 6-[4-methoxy-2-(trifluoromethoxy)phenyl]pyrazine 155

2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)- 6-[4-methoxy-2-(trifluoromethyl)phenyl]pyrazine 156

2-[4-chloro-2-(trifluoromethyl)phenyl]-3,6- diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 157

2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)- 6-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazine 158

2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)-6-(4-methoxy-2-methylphenyl)pyrazine 159

N-(1-ethylpropyl)-3-methoxy-5-[4-methoxy-2-(trifluoromethoxy)phenyl]-6-methylpyrazin-2- amine 160

N-(1-ethylpropyl)-3-methoxy-5-[4-methoxy-2-(trifluoromethyl)phenyl]-6-methylpyrazin-2- amine 161

5-[4-chloro-2-(trifluoromethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 162

N-(1-ethylpropyl)-3-methoxy-6-methyl-5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2- amine 163

N-(1-ethylpropyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methylpyrazin-2- amine 164

3,6-diethyl-N-(1-ethylpropyl)-5-[4-methyl-2-(trifluoromethyl)phenyl]pyrazin-2-amine 165

6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-[4-methyl-2-(trifluoromethyl)phenyl]pyrazin-2- amine 166

5-(4-tert-butyl-2,6-dimethylphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 167

5-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2- amine 168

2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)-6-(2-methoxy-4,6-dimethylphenyl)pyrazine 169

2-[2,4-bis(trifluoromethyl)phenyl]-3,6-diethyl5-(1-isopropyl-2-methylpropoxy)pyrazine 170

2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)- 6-[4-methyl-2-(trifluoromethyl)phenyl]pyrazine 171

3-ethyl-N-(1-ethylpropyl)-6-methoxy-5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2- amine 172

5-(2,4-dimethylphenyl)-3,6-diethyl-N-(1- ethylpropyl)pyrazin-2-amine 173

5-(2-chloro-4-fluorophenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 174

5-[4-chloro-2-(trifluoromethyl)phenyl]-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2- amine 175

5-(2,4-dimethylphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 176

5-(2-chloro-4-fluorophenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 177

5-(2-chloro-4-ethoxyphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 178

N-(1-ethylpropyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethyl)phenyl]-6-methylpyrazin-2- amine 179

5-(2-chloro-4-ethoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 180

5-(2,4-dimethylphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 181

3-ethyl-N-(1-ethylpropyl)-6-methoxy-5-[4-methyl-2-(trifluoromethyl)phenyl]pyrazin-2- amine 182

3-chloro-4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}phenol 183

O-(3-chloro-4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}phenyl)S- propyl(dithiocarbonate) 184

5-[2-chloro-4-(trifluoromethoxy)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 185

2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)- 6-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazine 186

2,5-diethyl-3-(4-fluoro-2-methoxyphenyl)-6-(1-isopropyl-2-methylpropoxy)pyrazine 187

2,5-diethyl-3-(1-ethylpropoxy)-6-[2-methoxy-4,6-bis(trifluoromethyl)phenyl]pyrazine 188

5-(2,6-dichlorophenyl)-3,6-diethyl-N-(1- ethylpropyl)pyrazin-2-amine 189

5-(2,6-dimethoxyphenyl)-3,6-diethyl-N-(1- ethylpropyl)pyrazin-2-amine190

5-(2,6-dimethylphenyl)-3,6-diethyl-N-(1- ethylpropyl)pyrazin-2-amine 191

3,6-diethyl-N-(1-ethylpropyl)-5-(4-fluoro-2-methoxyphenyl)pyrazin-2-amine 192

6-ethyl-N-(1-ethylpropyl)-5-(4-fluoro-2-methoxyphenyl)-3-methoxypyrazin-2-amine 193

3-ethyl-N-(1-ethylpropyl)-5-(4-fluoro-2-methoxyphenyl)-6-methoxypyrazin-2-amine 194

3-ethyl-N-(1-ethylpropyl)-6-methoxy-5-[4-(trifluoromethyl)phenyl]pyrazin-2-amine 195

5-(2-chloro-4-methylphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 196

2,5-diethyl-3-(1-ethylbutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazine 197

2,5-diethyl-3-(1-ethylpropoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]pyrazine 198

5-(2-chloro-4-methylphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 199

5-(2-chloro-4-methylphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 200

5-(4-chloro-2-methoxyphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 201

5-(4-chloro-2-methoxyphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 202

5-(4-chloro-2-methoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 203

5-(2-chloro-4-isopropoxyphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 204

O-(3-chloro-4-{3,6-diethyl-5-[(1-ethylpropyl)amino]pyrazin-2-yl}phenyl)S- propyl(dithiocarbonate) 205

5-(2,6-dimethylphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 206

5-(2,6-dimethoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 207

5-(4-chloro-2,6-dimethoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 208

5-(4-chloro-2,6-dimethoxyphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 209

5-(3,5-dichlorothien-2-yl)-3,6-diethyl-N-(1- ethylpropyl)pyrazin-2-amine210

5-(3,5-dichlorothien-2-yl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 211

2-(2,4-dimethoxyphenyl)-3,6-diethyl-5-(1- ethylbutoxy)pyrazine 212

2-(cyclopentyloxy)-5-(2,4-dimethoxyphenyl)- 3,6-diethylpyrazine 213

2,5-diethyl-3-(1-ethylbutoxy)-6-[2-methoxy-4-(trifluoromethyl)phenyl]pyrazine 214

2,5-diethyl-3-(1-ethylbutoxy)-6-[4-methoxy-2-(trifluoromethyl)phenyl]pyrazine 215

5-(4-tert-butyl-2,6-dimethylphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 216

5-(2,6-dichloro-4-methoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 217

5-[2-chloro-4-(difluoromethoxy)phenyl]-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine 218

5-(2,6-dimethoxy-4-methylphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 219

2-(2-chloro-4-methoxyphenyl)-3,6-diethyl-5- (1-ethylbutoxy)pyrazine 220

5-[4-(1,3-dioxolan-2-yl)-2,6- dimethoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 221

N-(1-ethylpropyl)-5-(4-fluoro-2-methoxyphenyl)-3-methoxy-6-methylpyrazin-2-amine 222

5-(2-chloro-4-fluorophenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 223

5-[2,4-bis(trifluoromethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 224

5-(4-chloro-2-methylphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 225

5-(4-chloro-2-methoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 226

5-(2,4-diethoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 227

5-(4-ethoxy-2-methoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 228

N-(1-ethylpropyl)-3-methoxy-5-(2-methoxy-4-methylphenyl)-6-methylpyrazin-2-amine 229

3-ethyl-N-(1-ethylpropyl)-6-methoxy-5-(2-methoxy-6-methylphenyl)pyrazin-2-amine 230

3-ethyl-N-(1-ethylpropyl)-6-methoxy-5-[4-methoxy-2-(trifluoromethyl)phenyl]pyrazin-2- amine 231

6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-(2-methoxy-6-methylphenyl)pyrazin-2-amine 232

N-(1-ethylpropyl)-3-methoxy-5-(2-methoxy-6- methylphenyl)pyrazin-2-amine233

5-[4-(difluoromethyl)-2,6-dimethoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6- methylpyrazin-2-amine 234

1-(4-{5-[(1-ethylpropyl)amino]-6-methoxy-3- methylpyrazin-2-yl}-3,5-dimethoxyphenyl)ethanol 235

1-(4-{5-[(1-ethylpropyl)amino]-6-methoxy-3- methylpyrazin-2-yl}-3,5-dimethoxyphenyl)ethanone 236

5-(2-chloro-4-methoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 237

2-[2,4-bis(trifluoromethyl)phenyl]-3,6-diethyl-5-(1-ethylbutoxy)pyrazine 238

2-(2-chloro-4-methoxyphenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 239

2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)- 6-[2-methoxy-4-(trifluoromethyl)phenyl]pyrazine 240

5-(2-chloro-4-ethoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 241

5-(2-chloro-4-isopropoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 242

5-(2-chloro-4-isopropoxyphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 243

2-(4-{5-[(1-ethylpropyl)amino]-6-methoxy-3- methylpyrazin-2-yl}-3,5-dimethoxyphenyl)propan-2-ol 244

2,5-diethyl-3-(1-ethylbutoxy)-6-(2-methoxy- 4,6-dimethylphenyl)pyrazine245

2,5-diethyl-3-(1-ethylbutoxy)-6-[4-methoxy-2-(trifluoromethoxy)phenyl]pyrazine 246

5-(4-chloro-2-ethoxyphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 247

5-(4-chloro-2-ethoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 248

3-ethyl-6-methoxy-N-(4-methoxybenzyl)-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin- 2-amine 249

5-(2,4-dimethoxyphenyl)-3-ethyl-6-methoxy-N-(4-methoxybenzyl)pyrazin-2-amine 250

2-(2,4-dichloro-6-methylphenyl)-3,6-diethyl-5- (1-ethylpropoxy)pyrazine251

2-(4-chloro-2,6-dimethoxyphenyl)-3,6-diethyl- 5-(1-ethylpropoxy)pyrazine252

3-ethyl-5-(2-ethyl-4-methoxyphenyl)-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 253

5-(2-ethyl-4-methoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 254

6-ethyl-5-(2-ethyl-4-methoxyphenyl)-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 255

5-[4-(benzyloxy)-2-isopropoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 256

5-(4-chloro-2-ethoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 257

N-(1-ethylpropyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-amine 258

3-chloro-4-{6-ethyl-5-[(1-ethylpropyl)amino]-3-methoxypyrazin-2-yl}phenol 259

3-chloro-4-{3-ethyl-5-[(1-ethylpropyl)amino]-6-methoxypyrazin-2-yl}phenol 260

5-(2-chloro-4-isopropoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 261

5-(2-chloro-4-methoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 262

5-[2-chloro-4-(difluoromethoxy)phenyl]-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2- amine 263

5-[2-chloro-4-(difluoromethoxy)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2- amine 264

5-[2-chloro-4-(1-ethylpropoxy)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2- amine 265

5-[2-chloro-4-(2-fluoroethoxy)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 266

5-[2-chloro-4-(difluoromethoxy)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 267

5-[2-chloro-4-(1-ethylpropoxy)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 268

3-(benzyloxy)-4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}phenol 269

5-[4-(but-3-enyloxy)-2-chlorophenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 270

5-(2,4-dimethoxyphenyl)-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2-amine 271

5-(2,4-dichlorophenyl)-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2-amine 272

N-(1-ethylpropyl)-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-3-methylpyrazin-2-amine 273

5-[2-chloro-4-(trifluoromethyl)phenyl]-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2- amine 274

5-[2′-chloro-4′,5-bis(trifluoromethyl)-1,1′-biphenyl-2-yl]-N-(1-ethylpropyl)-6-methoxy- 3-methylpyrazin-2-amine 275

N-(1-ethylpropyl)-6-methoxy-5-[2-methoxy-4-(trifluoromethyl)phenyl]-3-methylpyrazin-2- amine 276

5-(2-chloro-4-methylphenyl)-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2- amine 277

N-(1-ethylpropyl)-6-methoxy-3-methyl-5-(4- methylphenyl)pyrazin-2-amine278

N-(1-ethylpropyl)-5-(4-fluoro-2-methoxyphenyl)-6-methoxy-3-methylpyrazin- 2-amine 279

N-(1-ethylpropyl)-6-methoxy-3-methyl-5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2- amine 280

5-(2-ethyl-4-methoxyphenyl)-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2- amine 281

N-(1-ethylpropyl)-6-methoxy-3-methyl-5-[4-methyl-2-(trifluoromethyl)phenyl]pyrazin-2- amine 282

5-(2,4-dimethylphenyl)-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2-amine 283

5-(4-chloro-2,6-dimethoxyphenyl)-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2- amine 284

5-(4-chloro-2,6-dimethoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 285

2,5-diethyl-3-(2-ethyl-4-methoxyphenyl)-6-(1-isopropyl-2-methylpropoxy)pyrazine 286

2-(4-chloro-2,6-dimethoxyphenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 287

4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3-isopropoxyphenol 288

5-(2,4-diisopropoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 289

N-(1-ethylpropyl)-5-(2-isopropoxy-4-propoxyphenyl)-3-methoxy-6-methylpyrazin- 2-amine 290

5-(4-ethoxy-2-isopropoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 291

(3-chloro-4-{5-[(1-ethylpropyl)amino]-6- methoxy-3-methylpyrazin-2-yl}phenoxy)acetonitrile 292

5-(2-chloro-4-fluorophenyl)-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2- amine 293

5-[2-chloro-4-(1-ethylpropoxy)phenyl]-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2- amine 294

5-[4-(cyclopentyloxy)-2-isopropoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 295

5-[4-(allyloxy)-2-isopropoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 296

2-[2-chloro-4-(trifluoromethyl)phenyl]-3,6-diethyl-5-(1-ethylbutoxy)pyrazine 297

2-[2-chloro-4-(trifluoromethyl)phenyl]-3,6- diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 298

2-(4-chloro-2-methylphenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 299

N-(1-ethylpropyl)-5-[4-(1-fluoroethyl)-2,6-dimethoxyphenyl]-3-methoxy-6- methylpyrazin-2-amine 300

2-(2-chloro-4-fluorophenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 301

5-(2-chloro-4-{[(Z)-1-fluoro-2-iodoethenyl]oxy}phenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 302

5-[2-chloro-4-(2-methoxyethoxy)phenyl]-N-(1ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 303

5-(4-{[tert-butyl(dimethyl)silyl]oxy}-2-methoxyphenyl)-N-(1-ethylpropyl)-3-methoxy 6-methylpyrazin-2-amine 304

4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3-methoxyphenol 305

5-[4-(difluoromethoxy)-2-methoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 306

2-(2-chloro-4-fluorophenyl)-3,6-diethyl-5-(1- ethylpropoxy)pyrazine 307

2-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-5-methoxybenzaldehyde 308

5-{2-[(dimethylamino)methyl]-4- methoxyphenyl}-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine 309

N-(1-ethylpropyl)-3-methoxy-5-[4-methoxy-2-(morpholin-4-ylmethyl)phenyl]-6- methylpyrazin-2-amine 310

N-(1-ethylpropyl)-3-methoxy-5-[4-methoxy-2-(piperidin-1-ylmethyl)phenyl]-6- methylpyrazin-2-amine 311

(2-{5-[(1-ethylpropyl)amino]-6-methoxy-3- methylpyrazin-2-yl}-5-methoxyphenyl)methanol 312

1-(2-{5-[(1-ethylpropyl)amino]-6-methoxy-3- methylpyrazin-2-yl}-5-methoxyphenyl)ethanol 313

1-(2-{5-[(1-ethylpropyl)amino]-6-methoxy-3- methylpyrazin-2-yl}-5-methoxyphenyl)ethanone 314

5-[4-(difluoromethoxy)-2-methoxyphenyl]-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2- amine 315

3-chloro-4-[3,6-diethyl-5-(1- ethylpropoxy)pyrazin-2-yl]phenol 316

2-(2-chloro-4-ethoxyphenyl)-3,6-diethyl-5-(1- ethylpropoxy)pyrazine 317

2-(2-chloro-4-propoxyphenyl)-3,6-diethyl-5- (1-ethylpropoxy)pyrazine 318

2-(2-chloro-4-isopropoxyphenyl)-3,6-diethyl- 5-(1-ethylpropoxy)pyrazine319

2-(2-chloro-4-isobutoxyphenyl)-3,6-diethyl-5- (1-ethylpropoxy)pyrazine320

2-[2-chloro-4-(cyclopropylmethoxy)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine 321

2-(4-butoxy-2-chlorophenyl)-3,6-diethyl-5-(1- ethylpropoxy)pyrazine 322

{3-chloro-4-[3,6-diethyl-5-(1- ethylpropoxy)pyrazin-2-yl]phenoxy}acetonitrile 323

2-[2-chloro-4-(2-fluoroethoxy)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine 324

2-[2-chloro-4-(2-methoxyethoxy)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine 325

4-{6-ethyl-5-[(1-ethylpropyl)amino]-3-methoxypyrazin-2-yl}-3-methoxyphenol 326

5-(4-ethoxy-2-methoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2- amine 327

N-(1-ethylpropyl)-5-(4-isopropoxy-2-methoxyphenyl)-3-methoxy-6-methylpyrazin- 2-amine 328

3-ethyl-N-(1-ethylpropyl)-5-(4-isopropoxy-2-methoxyphenyl)-6-methoxypyrazin-2-amine 329

2-(4-{[tert-butyl(dimethyl)silyl]oxy}-2-isopropoxyphenyl)-3,6-diethyl-5-(1- ethylpropoxy)pyrazine 330

2-[2-chloro-4-(difluoromethoxy)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine 331

2-[4-(difluoromethoxy)-2-methoxyphenyl]-3,6diethyl-5-(1-ethylpropoxy)pyrazine 332

4-[3,6-diethyl-5-(1-ethylpropoxy)pyrazin-2- yl]-3-methoxyphenol 333

2-(4-ethoxy-2-methoxyphenyl)-3,6-diethyl-5- (1-ethylpropoxy)pyrazine 334

2,5-diethyl-3-(1-ethylpropoxy)-6-(4- isopropoxy-2-methoxyphenyl)pyrazine335

2,5-diethyl-3-(1-ethylbutoxy)-6-(4-fluoro-2- methylphenyl)pyrazine 336

2,5-diethyl-3-(4-fluoro-2-methylphenyl)-6-(1-isopropyl-2-methylpropoxy)pyrazine 337

2-(2,6-dimethoxyphenyl)-3,6-diethyl-5-(1- ethylpropoxy)pyrazine 338

2-(2,6-dimethoxyphenyl)-3,6-diethyl-5-(1- ethylbutoxy)pyrazine 339

2-(2,6-dimethoxyphenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 340

4-[3,6-diethyl-5-(1-ethylpropoxy)pyrazin-2- yl]-3-isopropoxyphenol 341

4-{3-ethyl-5-[(1-ethylpropyl)amino]-6-methoxypyrazin-2-yl}-3-methoxyphenol 342

5-[4-(difluoromethoxy)-2-methoxyphenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2- amine 343

5-(4-ethoxy-2-methoxyphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine 344

6-ethyl-N-(1-ethylpropyl)-5-(4-isopropoxy-2-methoxyphenyl)-3-methoxypyrazin-2-amine 345

2-(2,4-diisopropoxyphenyl)-3,6-diethyl-5-(1- ethylpropoxy)pyrazine 346

N-cyclopentyl-5-(2,4-dichlorophenyl)-3,6- diethylpyrazin-2-amine 347

2,5-diethyl-3-(2-ethyl-4-methoxyphenyl)-6-(1- ethylpropoxy)pyrazine 348

4-[3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazin-2-yl]-3-ethylphenol 349

2-(4-ethoxy-2-ethylphenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 350

2,5-diethyl-3-(2-ethyl-4-isopropoxyphenyl)-6-(1-isopropyl-2-methylpropoxy)pyrazine 351

2-[4-(cyclopentyloxy)-2-ethylphenyl]-3,6- diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 352

2-(4-ethoxy-2-isopropoxyphenyl)-3,6-diethyl- 5-(1-ethylpropoxy)pyrazine353

2-(2,4-dimethoxyphenyl)-3,6-diethyl-5-(1- propylbutoxy)pyrazine 354

2-(2-chloro-4-methoxyphenyl)-3,6-diethyl-5- (1-propylbutoxy)pyrazine 355

3-ethyl-N-(1-ethylpropyl)-5-[4-fluoro-2-(trifluoromethyl)phenyl]-6-methoxypyrazin-2- amine 356

3-chloro-4-{3,6-diethyl-5-[(1- ethylpropyl)amino]pyrazin-2-yl}phenol 357

2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)- 6-[2-methoxy-4,6-bis(trifluoromethyl)phenyl]pyrazine 358

2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)- 6-mesitylpyrazine 359

2-(2,4-dimethylphenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine 360

2,5-diethyl-3-(1-ethylpropoxy)-6- mesitylpyrazine 361

2,5-diethyl-3-(1-ethylpropoxy)-6-[4-methoxy-2-(trifluoromethyl)phenyl]pyrazine 362

2,5-diethyl-3-(1-ethylpropoxy)-6-(4-methoxy- 2-methylphenyl)pyrazine 363

5-[2,4-bis(trifluoromethyl)phenyl]-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 364

5-(4-chloro-2-methylphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine 365

2,5-diethyl-3-[2-methoxy-4- (trifluoromethoxy)phenyl]-6-(1-propylbutoxy)pyrazine 366

2,5-diethyl-3-[4-methoxy-2- (trifluoromethoxy)phenyl]-6-(1-propylbutoxy)pyrazine 367

2,5-diethyl-3-(4-fluoro-2-methylphenyl)-6-(1- propylbutoxy)pyrazine 368

2,5-diethyl-3-[2-methoxy-4- (trifluoromethyl)phenyl]-6-(1-propylbutoxy)pyrazine 369

6-chloro-5-[2-methoxy-4- (trifluoromethoxy)phenyl]pyrazin-2-amine 370

2-(2,4-dimethoxyphenyl)-3,6-diethyl-5-(2- methylbutyl)pyrazine 371

2-(2-chloro-4-ethoxyphenyl)-3,6-diethyl-5-(1- ethylbutoxy)pyrazine 372

2-(2-chloro-4-isopropoxyphenyl)-3,6-diethyl- 5-(1-ethylbutoxy)pyrazine373

2-(4-butoxy-2-chlorophenyl)-3,6-diethyl-5-(1- ethylbutoxy)pyrazine 374

2-[2-chloro-4-(cyclopentyloxy)phenyl]-3,6-diethyl-5-(1-ethylbutoxy)pyrazine 375

2-[2-chloro-4-(difluoromethoxy)phenyl]-3,6-diethyl-5-(1-ethylbutoxy)pyrazine 376

N-(1-ethylpropyl)-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-amine 377

3-bromo-N-(1-ethylpropyl)-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin- 2-amine 378

3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-amine 379

2-ethyl-3-(1-ethylpropoxy)-5-methoxy-6-[2- methoxy-4-(trifluoromethoxy)phenyl]pyrazine 380

2-(4-{[tert-butyl(dimethyl)silyl]oxy}-2- ethoxyphenyl)-3,6-diethyl-5-(1-ethylpropoxy)pyrazine 381

4-[3,6-diethyl-5-(1-ethylpropoxy)pyrazin-2- yl]-3-ethoxyphenol 382

2-(2,4-diethoxyphenyl)-3,6-diethyl-5-(1- ethylpropoxy)pyrazine 383

2-(2-ethoxy-4-isopropoxyphenyl)-3,6-diethyl- 5-(1-ethylpropoxy)pyrazine384

6-methoxy-5-[2-methoxy-4- (trifluoromethoxy)phenyl]pyrazin-2-ylformamide 385

3-ethyl-N-(1-ethylpropyl)-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-amine 4- oxide 386

6-chloro-3-ethyl-N-(1-ethylpropyl)-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin- 2-amine 387

2,5-diethyl-3-(2-ethylbutyl)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazine 388

2-[2-chloro-4-(trifluoromethyl)phenyl]-3,6-diethyl-5-(2-ethylbutyl)pyrazine 389

2-(2-ethoxy-4-propoxyphenyl)-3,6-diethyl-5- (1-ethylpropoxy)pyrazine 390

2,5-diethyl-3-(1-ethylpropoxy)-6-(2- isopropoxy-4-propoxyphenyl)pyrazine391

N-[6-chloro-5-(4-chloro-2,6- dimethoxyphenyl)pyrazin-2-yl]acetamide 392

2-(sec-butylthio)-3-ethyl-6-methoxy-5-[2- methoxy-4-(trifluoromethoxy)phenyl]pyrazine 393

2-(sec-butylthio)-5-(2,4-dichlorophenyl)-3,6- diethylpyrazine 394

2-(sec-butylthio)-5-(2,4-dimethoxyphenyl)- 3,6-diethylpyrazine 395

3-ethyl-N-(1-ethylpropyl)-5-[2-methoxy-4- (trifluoromethoxy)phenyl]-6-(methylthio)pyrazin-2-amine 396

5-(4-chloro-2,6-dimethoxyphenyl)-6- methoxypyrazin-2-amine

[0408] The invention and the manner and process of making and using it,are now described in such full, clear, concise and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt, thereof, wherein: Ar issubstituted phenyl, optionally substituted napthyl, or an optionallysubstituted heterocyclic group having from 1 to 3 rings, and 3 to 8 ringmembers in each ring and 1 to about 3 hetero atoms; R₁ and R₃ are eachindependently hydrogen, halogen, cyano, nitro, amino, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted mono or dialkylamino,optionally substituted alkoxy, optionally substituted alkylthio,optionally substituted alkylsulfinyl, or optionally substitutedalkylsulfonyl; and R₂ is halogen, cyano, nitro, amino, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted alkylamino, optionallysubstituted alkoxy, optionally substituted alkylthio, optionallysubstituted alkylsulfinyl, or optionally substituted alkylsulfonyl; withthe proviso that if Ar is phenyl substituted with halogen, napthyl, ornaphthyl substituted with halogen, then the compounds where R₃ ishydrogen or amino are excluded.
 2. A compound according to claim 1,wherein: Ar is substituted phenyl, optionally substituted naphthyl, oran optionally substituted heterocyclic group having at least onenitrogen ring atom or at least one sulfur ring atom.
 3. A compound ofthe formula:

or a pharmaceutically acceptable salt thereof, wherein: R₁ is selectedfrom H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halogen, CN, C₁₋₄haloalkyl, trifluoromethyl, trifluoromethoxy, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), and S(O)_(n)(C₁₋₄ alkyl); R₂ isselected from the group consisting of —XR_(A) and Y, wherein —X, R_(A),and Y are defined below; and R₃ is selected from the group consisting ofhydrogen, halogen, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)(C₁₋₄ alkyl), and —S(O)_(n)(C₁₋₄ alkyl), haloalkyl,trifluoromethyl, trifluoromethoxy, —XR_(A) and Y; R₄ is absent or anoxygen atom; Ar is phenyl, mono-, di-, or tri-substituted with R_(C), orAr is selected from the group consisting of: naphthyl, pyridyl,pyridonyl, pyrimidinyl, and thiophenyl, each of which is unsubstitutedor mono-, di-, or tri-substituted with R_(C); with the proviso that ifAr is phenyl substituted with halogen, napthyl, or naphthyl substitutedwith halogen, then the compounds where R₃ is hydrogen are excluded;R_(A) and R_(B), which may be the same or different, are independentlyselected at each occurrence from the group consisting of: hydrogen andstraight, branched, or cyclic alkyl groups consisting of 1 to 8 carbonatoms, each of which alkyl groups may contain one or more double ortriple bonds, and may be further substituted with one or moresubstituent(s) selected from oxo, hydroxy, halogen, —O(C₁₋₄ alkyl),—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)C(═O)(C₁₋₄ alkyl), —NHS(O).(C₁₋₄ alkyl), —S(O)_(n)(C₁₋₄alkyl), —S(O)_(n)NH(C₁₋₄ alkyl), —S(O).N(C₁₋₄ alkyl)(C₁₋₄ alkyl), and Z;R_(C) is independently selected at each occurrence from the groupconsisting of halogen, cyano, haloalkyl, trifluoromethyl,trifluoromethoxy, hydroxy, amino, and C₁₋₆ alkyl optionally substitutedwith 0-2 R_(D), C₂₋₆ alkenyl substituted with 0-2 R_(D), C₁₋₄ alkynylsubstituted with 0-2 R_(D), C₃₋₇ cycloalkyl substituted with 0-2 R_(D),(C₃₇ cycloalkyl)C₁₋₄ alkyl substituted with 0-2 R_(D), —O(C₁₋₄ alkyl)substituted with 0-2 R_(D), —NH(C₁₋₄ alkyl) substituted with 0-2 R_(D),—N(C₁₋₄ alkyl)(C₁₋₄ alkyl) each independently substituted with 0-2R_(D), —XR_(A), and Y; R_(D) is independently selected at eachoccurrence the group consisting of halogen, hydroxy, cyano, C₁₋₄alkyl,—O(C₁₋₄alkyl), —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)(C₁₋₄alkyl), morpholino,pyrrolidino, piperidino, thiomorpholino, piperazino,4-hydroxypiperidino, —S(O),(C₁₋₄alkyl), trifluoromethyl,trifluoromethoxy, CO(C₁₋₄alkyl), CONH(C₁₋₄alkyl), CON(C₁₋₄alkyl)(C₁₋₄alkyl), —XR_(A), and Y; X is independently selected at each occurrencefrom the group consisting of —CH₂—, —CHR_(B)—, —O—, —C(═O)—, —C(═O)O—,—S(O)_(n)-, —NH—, —NR_(B)—, —C(═O)NH—, —C(═O)NR_(B)—, —S(O)_(n)NH-,—S(O)_(n)NR_(B)—, —OC(═S)S—, —NHC(═O)—, —NR_(B)C(═O)—, —NHS(O)_(n)-,—OSiH,(C₁₋₄alkyl)_(2-n)-, and —NR_(B)S(O)_(n)-; and Y and Z areindependently selected at each occurrence from the group consisting of:3- to 7-membered carbocyclic and heterocyclic groups, which aresaturated, unsaturated, or aromatic, which may be substituted with oneor more substituents selected from halogen, haloalkyl, oxo, hydroxy,amino, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄alkyl), and —S(O)_(n)(C₁₋₄ alkyl), and said 3- to 7-memberedheterocyclic groups contain one or more heteroatom(s) selected from N,O, and S, with the point of attachment being either carbon or nitrogen;and n is independently selected at each occurrence from 0, 1, and
 2. 4.A compound of according to claim 1 wherein Ar is substituted phenyl. 5.A compound according to claim 3, wherein R₄ is absent and Ar is phenyl,mono-, di-, or tri-substituted with R_(C).
 6. A compound according toclaim 3 wherein R₄ is absent and Ar is phenyl, mono-, di-, ortri-substituted with R_(C), and R₁ and R₃ are independently selectedfrom the group consisting of hydrogen, halogen, methyl, ethyl, ethoxyand methoxy.
 7. A compound according to claim 3 wherein R₄ is absent andAr is phenyl, mono-, di-, or tri-substituted with R_(C); and R_(A) andR_(B), which may be the same or different, are independently straight,branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, whichmay contain one or more double or triple bonds.
 8. A compound accordingto claim 3 wherein R₄ is absent and Ar is phenyl mono-, di-, ortri-substituted with R_(C); R_(A) and R_(B), which may be the same ordifferent, are independently selected at each occurrence from the groupconsisting of: straight, branched, and cyclic alkyl groups having from 1to 8 carbon atoms, which may contain one or more double or triple bonds;and R₁ and R₃ are independently selected from the group consisting ofhydrogen, halogen, methyl, ethyl, ethoxy, and methoxy.
 9. A compound ofthe Formula:

wherein R_(X) and R_(Y) are the same or different and are independentlyselected straight, branched, or cyclic alkyl groups having from 1 to 8carbon atoms, which may contain one or more double or triple bonds, eachof which may be further substituted with one or more substituent(s)independently selected from hydroxy, halogen, —O(C₁₋₄ alkyl), —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), : hydrogen and straight, branched,or cyclic alkyl groups consisting of 1 to 8 carbon atoms, each of whichalkyl groups may contain one or more double or triple bonds, and may befurther substituted with one or more substituent(s) selected from oxo,hydroxy, halogen, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄alkyl), —NHC(O)(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)C(═O)(C₁₋₄ alkyl),—NHS(O)_(n)(C₁₋₄ alkyl), —S(O),(C₁₋₄ alkyl), —S(O)_(n)NH(C₁₋₄ alkyl),—S(O)_(n)N(C₁₋₄ alkyl)(C₁₋₄ alkyl), Z, and phenyl, optionally mono-, di-or tri-substituted with substituents independently chosen from C₁₋₄alkoxy, C₁₋₄ alkyl, halogen, CF3, OCF3, OCHF2, OH, and CN; and Z isindependently selected at each occurrence from the group consisting of:3- to 7-membered carbocyclic and heterocyclic groups, which aresaturated, unsaturated, or aromatic, which may be substituted with oneor more substituents selected from halogen, haloalkyl, oxo, hydroxy,amino, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄alkyl), and —S(O)_(n)(C₁₋₄ alkyl), and said 3- to 7-memberedheterocyclic groups contain one or more heteroatom(s) selected from N,O, and S, with the point of attachment being either carbon or nitrogen;and n is independently selected at each occurrence from 0, 1, and
 2. 10.A compound according to claim 9, wherein Ar is phenyl, mono-, di-, ortri-substituted with R_(C); and R₁ and R₃ are independently selectedfrom the group consisting of hydrogen, halogen, methyl, ethyl, ethoxyand methoxy.
 11. A compound according to claim 9, wherein: R₁ and R₃ areindependently chosen from halogen, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl, trifluoromethyl, andtrifluoromethoxy; and Ar is phenyl, which is mono-, di-, ortrisubstituted with one or more substituent(s) independently selectedfrom: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy,hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy),mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.12. A compound according to claim 9, wherein: R_(X) is hydrogen; R_(Y)is chosen from the group consisting of: straight, branched, or cyclicalkyl groups having from 1 to 8 carbon atoms, which may contain one ormore double or triple bonds; R₁ and R₃ are independently chosen fromhalogen, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)(C₁₋₄ alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy;and Ar is phenyl, which is mono-, di-, or trisubstituted withsubstituent(s) independently selected from: halogen, cyano, haloalkyl,trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C₁₋₆ alkyl,C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy), mono- or di(C₁₋₄)amino(C₁₋₄alkoxy),and mono- or di(C₁₋₄ alkyl)amino.
 13. A compound according to claim 9,wherein: R_(X) is hydrogen; R_(Y) is chosen from the group consistingof: straight, branched, or cyclic alkyl groups having from 1 to 8 carbonatoms, which may contain one or more double or triple bonds; R₁ and R₃are independently chosen from halogen, C₁₋₄ alkyl, —O(C₁₋₄ alkyl),—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl, trifluoromethyl,and trifluoromethoxy; and

and one, two or three of positions 2, 4, and 6 are substituted withsubstituent(s) independently selected from: halogen, cyano, haloalkyl,trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C₁₋₆ alkyl,C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy), mono- or di(C₁₋₄)amino(C₁₋₄alkoxy),and mono- or di(C₁₋₄ alkyl)amino.
 14. A compound according to claim 9,wherein: R_(X) is hydrogen; R_(Y) is chosen from the group consistingof: straight, branched, or cyclic alkyl groups having from 1 to 8 carbonatoms, which may contain one or more double or triple bonds; R₁ and R₃are independently chosen from halogen, C₁₋₄ alkyl, —O(C₁₋₄ alkyl),—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl, trifluoromethyl,and trifluoromethoxy; and

which is substituted at positions 2 and 4 with substituentsindependently selected from: halogen, cyano, haloalkyl, trifluoromethyl,trifluoromethoxy, hydroxy, amino, and C₁₋₄ alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy(C₁₋₄alkoxy), mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- ordi(C₁₋₄ alkyl)amino.
 15. A compound according to claim 9 of the formula:

wherein: R₁ and R₃ are independently chosen at each occurrence fromhalogen, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)(C₁₋₄ alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy;and

and is substituted at positions 2 and 4 with substituents independentlyselected from: halogen, cyano, haloalkyl, trifluoromethyl,trifluoromethoxy, hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy(C₁₋₄alkoxy), mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- ordi(C₁₋₄ alkyl)amino.
 16. A compound according to claim 9 of the formula:

wherein R is independently selected at each occurrence from the groupconsisting of: hydrogen, halogen, cyano, haloalkyl, trifluoromethyl,trifluoromethoxy, hydroxy, amino, C₁₋₆alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy(C₁₋₄alkoxy), mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- ordi(C₁₋₄ alkyl)amino; and R₁ and R₃ are independently chosen fromhalogen, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)(C₁₋₄ alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy.17. A compound according to claim 9 wherein Ar is phenyl, which ismono-, di-, or tri-substituted with R_(C); R_(X) and R_(Y), which may bethe same or different, are independently selected at each occurrencefrom the group consisting of: straight, branched, and cyclic alkylgroups having from 1 to 8 carbon atoms, which may contain one or moredouble or triple bonds; and R₁ and R₃ are independently selected fromthe group consisting of hydrogen, halogen, methyl, ethyl, ethoxy, andmethoxy.
 18. A compound according to claim 3 of the formula:

wherein R_(X) and R_(y) are independently hydrogen or C₁₋₈ alkyl; orNR_(X)R_(Y) is:

wherein z is 0 or
 1. 19. A compound of the Formula:

wherein: R_(X) is chosen from the group consisting of: straight,branched, or cyclic alkyl groups, including (cycloalkyl)alkyl groups,having from 1 to 8 carbon atoms, which groups may contain one or moredouble or triple bonds, each of which groups may be further substitutedwith one or more substituent(s) independently selected from oxo,hydroxy, halogen, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(CI alkyl)(C₁₋₄alkyl), —NHC(O)(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)C(═O)(C₁₋₄ alkyl),—NHS(O),(C₁₋₄ alkyl), —S(O)_(n)(C₁₋₄ alkyl), —S(O)_(n)(H(C₁₋₄ alkyl),—S(O)_(n)((C₁₋₄ alkyl)(C₁₋₄ alkyl), Z, and phenyl, optionally mono-, di-or tri-substituted with substituents independently chosen from C1-4alkoxy, C1-4 alkyl, halogen, CF3, OCF3, OCHF2, OH, and CN; and Z isindependently selected at each occurrence from the group consisting of:3- to 7-membered carbocyclic and heterocyclic groups, which aresaturated, unsaturated, or aromatic, which may be substituted with oneor more substituents selected from halogen, haloalkyl, oxo, hydroxy,amino, C₁₋₄ alkyl, —O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄alkyl), and —S(O)_(n)(C₁₋₄ alkyl), and said 3- to 7-memberedheterocyclic groups contain one or more heteroatom(s) selected from N,O, and S, with the point of attachment being either carbon or nitrogen;and n is independently selected at each occurrence from 0, 1, and
 2. 20.A compound according to claim 19, wherein: R_(X) is selected fromstraight, branched, or cyclic alkyl groups containing of 1 to 8 carbonatoms, which may contain one or more double or triple bonds; and; R₁ andR₃ are independently chosen from halogen, C₁₋₄ alkyl, —O(C₁₋₄ alkyl),—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl, trifluoromethyl,and trifluoromethoxy; and Ar is phenyl, which is mono-, di-, ortrisubstituted with one or more substituent(s) independently selectedfrom: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy,hydroxy, amino, and C₁₋₆ alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy),mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.21. A compound according to claim 20, wherein:

and is substituted at substituted at one, two, or three of positions 2,4, and 6 with substituent(s)independently selected from: halogen, cyano,haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C₁₋₆alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy), mono- ordi(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.
 22. Acompound according to claim 20, wherein:

and is substituted at positions 2 and 4 with substituents independentlyselected from: halogen, cyano, haloalkyl, trifluoromethyl,trifluoromethoxy, hydroxy, amino, C₁₋₆ alkyl, C₁₋₄alkoxy,C₁₋₄alkoxy(C₁₋₄alkoxy), mono- or di(C₁₋₄)amino(C₁₋₄alkoxy), and mono- ordi(C₁₋₄alkyl)amino.
 23. A compound according to claim 19, of theformula:

wherein: R₁ and R₃ are independently chosen from halogen, C₁₋₄ alkyl,—O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)(C₁₋₄ alkyl), haloalkyl,trifluoromethyl, and trifluoromethoxy; and

and is substituted at substituted at one, two, or three of positions 2,4, and 6 with substituent(s)independently selected from: halogen, cyano,haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C₁₋₆alkyl, C₁₋₄alkoxy, C₁₋₄alkoxy(C₁₋₄alkoxy), mono- ordi(C₁₋₄)amino(C₁₋₄alkoxy), and mono- or di(C₁₋₄ alkyl)amino.
 24. Acompound according to claim 19 wherein R₁ and R₃ are independentlyselected from the group consisting of hydrogen, halogen, methyl, ethyl,ethoxy and methoxy.
 25. A compound according to claim 3 of the formula:

wherein A is NR_(A) or O.
 26. A compound according to claim 1 wherein,in a standard in vitro CRF receptor binding assay the compound exhibitsan IC₅₀ value less than or equal to 1 micromolar.
 27. A method formodulating CRF receptor function, comprising administering to a patientin need of such modulation an effective amount of a compound ofaccording to claim
 1. 28. A method for treating a CNS disorder ordisease, comprising administering to a patient in need of such treatmentan effective amount of a compound according to claim
 1. 29. The methodof claim 28 wherein the CNS disorder or disease is an anxiety disorder,stress-related disorder, or eating disorder.
 30. A compound according toclaim 1, wherein in a standard in vitro sodium channel functional assaythe compound does not show any statistically significant activity at thep<0.05 level of significance.
 31. A method of claim 28 wherein the CNSdisease or disorder is depression or a bipolar disorder.
 32. A method ofclaim 28 wherein the CNS disease or disorder is anorexia nervosa,bulimia nervosa, or obesity.
 33. A method according to claim 28 whereinin a standard in vitro CRF receptor binding assay the compound exhibitsan IC₅₀ value less than or equal to 1 micromolar.
 34. A method accordingto claim 28 wherein in a standard in vitro CRF receptor binding assaythe compound exhibits an IC₅₀ value less than or equal to 100 nanomolar.35. A method according to claim 28 wherein in a standard in vitro CRFreceptor binding assay the compound exhibits an IC₅₀ value less than orequal to 10 nanomolar.
 36. A method according to claim 28 wherein thepatient is a human.
 37. A method for localizing CRF receptors is tissuesection samples comprising: contacting with a sample of tissue adeteactably-labelled compound of claim 1 under conditions that permitbinding of the compound to CRF receptors within the sample of tissue;washing the tissue sample to remove unbound compound; and detectingremaining bound compound.
 38. A method of inhibiting the binding of CRFto a CRF1 Receptor which comprises: contacting a solution comprising CRFand a compound of claim 3 with a cell the receptor, wherein the compoundis present in the solution at a concentration sufficient to inhibit CRFbinding to IMR32 cells in vitro.
 39. A method for altering thesignal-transducing activity of a CRF1 receptor, the method comprisingcontacting cells expressing the receptor with a compound according toclaim
 3. 40. A method of modulating G-protein coupled receptor function,the method comprising exposing cells expressing a G-protein coupledreceptor to an effective amount of a compound according to claim
 3. 41.A method according to claim 40, wherein the G-coupled protein receptoris a CRF1 receptor.
 42. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of a compoundaccording to claim
 1. 43. A packaged pharmaceutical compositioncomprising a pharmaceutical composition of claim 42 in a container andinstructions for using the composition to treat a patient suffering froman anxiety disorder, a stress-related disorder, or an eating disorder.44. A compound according to claim 3, named5-(2,4-dimethoxyphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.45. A compound according to claim 3, named5-[4-bromo-2-(trifluoromethoxy)phenyl]-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine.46. A compound according to claim 3, named3-ethyl-N-(1-ethylpropyl)-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-amine.
 47. A compound according to claim 3, named5-(4-chloro-2-methylphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.48. A compound according to claim 3, named5-[2-chloro-4-(trifluoromethyl)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.49. A compound according to claim 3, named2-[2,4-bis(trifluoromethyl)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.50. A compound according to claim 3, named3,6-diethyl-N-(1-ethylpropyl)-5-(2-naphthyl)pyrazin-2-amine.
 51. Acompound according to claim 3, named5-[4-chloro-2-(trifluoromethyl)phenyl]-3,6-diethyl-N-1-ethylpropyl)pyrazin-2-amine.
 52. A compound according to claim 3,named3,6-diethyl-N-(1-ethylpropyl)-5-[2-methoxy-6-(trifluoromethoxy)phenyl]pyrazin-2-amine.53. A compound according to claim 3, named5-(2-chloro-4-methoxyphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.54. A compound according to claim 3, named5-(2,6-dichloro-4-methoxyphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine.
 55. A compound according to claim 3,named3,6-diethyl-N-(1-ethylpropyl)-5-(3-methyl-1,1′-biphenyl-4-yl)pyrazin-2-amine.56. A compound according to claim 3, named5-[2,4-bis(trifluoromethyl)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.57. A compound according to claim 3, named2-(2,4-dichlorophenyl)-3,6-diethyl-5-(1-methylbutoxy)pyrazine.
 58. Acompound according to claim 3, named2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)-6-[4-methoxy-2-(trifluoromethoxy)phenyl]pyrazine.59. A compound according to claim 3, named2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)-6-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazine.60. A compound according to claim 3, named5-[4-chloro-2-(trifluoromethyl)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.61. A compound according to claim 3, namedN-(1-ethylpropyl)-3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]-6-methylpyrazin-2-amine.62. A compound according to claim 3, named5-[4-chloro-2-(trifluoromethyl)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.
 63. A compound according toclaim 3, named3-ethyl-N-(1-ethylpropyl)-6-methoxy-5-[2-methyl-4-(trifluoromethoxy)phenyl]pyrazin-2-amine.64. A compound according to claim 3, named5-(2,4-dimethylphenyl)-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.65. A compound according to claim 3, named5-(2-chloro-4-ethoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.66. A compound according to claim 3, namedO-(3-chloro-4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}phenyl)S-propyl (dithiocarbonate).
 67. A compound according to claim 3, named2,5-diethyl-3-(1-ethylpropoxy)-6-[2-methoxy-4,6-bis(trifluoromethyl)phenyl]pyrazine.68. A compound according to claim 3, named3,6-diethyl-N-(1-ethylpropyl)-5-(4-fluoro-2-methoxyphenyl)pyrazin-2-amine.69. A compound according to claim 3, named5-(2-chloro-4-methylphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine.70. A compound according to claim 3, named5-(4-chloro-2-methoxyphenyl)-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine.71. A compound according to claim 3, namedO-(3-chloro-4-{3,6-diethyl-5-[(1-ethylpropyl)amino]pyrazin-2-yl}phenyl)S-propyl (dithiocarbonate).
 72. A compound according to claim 3, named5-(4-chloro-2,6-dimethoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.73. A compound according to claim 3, named2-(2,4-dimethoxyphenyl)-3,6-diethyl-5-(1-ethylbutoxy)pyrazine.
 74. Acompound according to claim 3, named5-[4-(1,3-dioxolan-2-yl)-2,6-dimethoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.75. A compound according to claim 3, named5-(4-ethoxy-2-methoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.76. A compound according to claim 3, named6-ethyl-N-(1-ethylpropyl)-3-methoxy-5-(2-methoxy-6-methylphenyl)pyrazin-2-amine.77. A compound according to claim 3, named2-(2-chloro-4-methoxyphenyl)-3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazine.78. A compound according to claim 3, named2-(4-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-3,5-dimethoxyphenyl)propan-2-ol.79. A compound according to claim 3, named5-(4-chloro-2-ethoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.80. A compound according to claim 3, named3-ethyl-5-(2-ethyl-4-methoxyphenyl)-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.81. A compound according to claim 3, named5-(4-chloro-2-ethoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.82. A compound according to claim 3, named5-(2-chloro-4-isopropoxyphenyl)-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.83. A compound according to claim 3, named5-[2-chloro-4-(1-ethylpropoxy)phenyl]-6-ethyl-N-(1-ethylpropyl)-3-methoxypyrazin-2-amine.84. A compound according to claim 3, named5-[2-chloro-4-(1-ethylpropoxy)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.85. A compound according to claim 3, named5-(2,4-dichlorophenyl)-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2-amine.86. A compound according to claim 3, named5-[2′-chloro-4′,5-bis(trifluoromethyl)-1,1′-biphenyl-2-yl]-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2-amine.87. A compound according to claim 3, namedN-(1-ethylpropyl)-5-(4-fluoro-2-methoxyphenyl)-6-methoxy-3-methylpyrazin-2-amine.88. A compound according to claim 3, named5-(2,4-dimethylphenyl)-N-(1-ethylpropyl)-6-methoxy-3-methylpyrazin-2-amine.89. A compound according to claim 3, named2,5-diethyl-3-(2-ethyl-4-methoxyphenyl)-6-(1-isopropyl-2-methylpropoxy)pyrazine.90. A compound according to claim 3, named5-(4-ethoxy-2-isopropoxyphenyl)-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.91. A compound according to claim 3, named5-[2-chloro-4-(1-ethylpropoxy)phenyl]-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.92. A compound according to claim 3, named2-[2-chloro-4-(trifluoromethyl)phenyl]-3,6-diethyl-5-(1-ethylbutoxy)pyrazine.93. A compound according to claim 3, namedN-(1-ethylpropyl)-5-[4-(1-fluoroethyl)-2,6-dimethoxyphenyl]-3-methoxy-6-methylpyrazin-2-amine.
 94. A compound according to claim 3,named5-[2-chloro-4-(2-methoxyethoxy)phenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.95. A compound according to claim 3, named5-[4-(difluoromethoxy)-2-methoxyphenyl]-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.96. A compound according to claim 3, named 5-{2-[(dimethylamino)methyl]-4-methoxyphenyl}-N-(1-ethylpropyl)-3-methoxy-6-methylpyrazin-2-amine.97. A compound according to claim 3, named(2-{5-[(1-ethylpropyl)amino]-6-methoxy-3-methylpyrazin-2-yl}-5-methoxyphenyl)methanol.98. A compound according to claim 3, named5-[4-(difluoromethoxy)-2-methoxyphenyl]-3-ethyl-N-(1-ethylpropyl)-6-methoxypyrazin-2-amine.99. A compound according to claim 3, named2-(2-chloro-4-propoxyphenyl)-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.100. A compound according to claim 3, named2-[2-chloro-4-(cyclopropylmethoxy)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.101. A compound according to claim 3, named2-[2-chloro-4-(2-fluoroethoxy)phenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.102. A compound according to claim 3, namedN-(1-ethylpropyl)-5-(4-isopropoxy-2-methoxyphenyl)-3-methoxy-6-methylpyrazin-2-amine.103. A compound according to claim 3, named2-(4-{[tert-butyl(dimethyl)silyl]oxy}-2-isopropoxyphenyl)-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.
 104. A compound according toclaim 3, named2-(4-ethoxy-2-methoxyphenyl)-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.105. A compound according to claim 3, named2-(2,6-dimethoxyphenyl)-3,6-diethyl-5-(1-ethylbutoxy)pyrazine.
 106. Acompound according to claim 3, named4-{3-ethyl-5-[(1-ethylpropyl)amino]-6-methoxypyrazin-2-yl}-3-methoxyphenol.
 107. A compound according to claim 3, named6-ethyl-N-(1-ethylpropyl)-5-(4-isopropoxy-2-methoxyphenyl)-3-methoxypyrazin-2-amine.108. A compound according to claim 3, named4-[3,6-diethyl-5-(1-isopropyl-2-methylpropoxy)pyrazin-2-yl]-3-ethylphenol.109. A compound according to claim 3, named3-ethyl-N-(1-ethylpropyl)-5-[4-fluoro-2-(trifluoromethyl)phenyl]-6-methoxypyrazin-2-amine.110. A compound according to claim 3, named2,5-diethyl-3-(1-isopropyl-2-methylpropoxy)-6-mesitylpyrazine.
 111. Acompound according to claim 3, named2,5-diethyl-3-(1-ethylpropoxy)-6-(4-methoxy-2-methylphenyl)pyrazine.112. A compound according to claim 3, named2,5-diethyl-3-[4-methoxy-2-(trifluoromethoxy)phenyl]-6-(1-propylbutoxy)pyrazine.113. A compound according to claim 3, named6-chloro-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-amine.
 114. Acompound according to claim 3, named2-(4-butoxy-2-chlorophenyl)-3,6-diethyl-5-(1-ethylbutoxy)pyrazine. 115.A compound according to claim 3, named3-bromo-N-(1-ethylpropyl)-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-amine.116. A compound according to claim 3, named2-(4-{[tert-butyl(dimethyl)silyl]oxy}-2-ethoxyphenyl)-3,6-diethyl-5-(1-ethylpropoxy)pyrazine.
 117. A compound according toclaim 3, named6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-ylformamide.118. A compound according to claim 3, named2,5-diethyl-3-(2-ethylbutyl)-6-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazine.119. A compound according to claim 3, named2,5-diethyl-3-(1-ethylpropoxy)-6-(2-isopropoxy-4-propoxyphenyl)pyrazine.120. A compound according to claim 3, named2-(sec-butylthio)-5-(2,4-dimethoxyphenyl)-3,6-diethylpyrazine.
 121. Acompound according to claim 3, named5-(4-chloro-2,6-dimethoxyphenyl)-6-methoxypyrazin-2-amine.
 122. Acompound according to claim 3, named3,6-diethyl-N-(1-ethylpropyl)-5-(2-methyl-4-chlorophenyl)pyrazin-2-amine.123. A compound according to claim 3, named3,6-diethyl-N-(1-ethylpropyl)-5-(2-methyl-4-fluorophenyl)pyrazin-2-amine.124. A compound according to claim 3, named3,6-diethyl-N,N-(2-methoxyethyl)-5-(2,4-dichlorophenyl)pyrazin-2-amine.125. A compound according to claim 3, named3,6-diethyl-N-propyl-N-(cyclopropylmethyl)-5-(2,4-dichlorophenyl)pyrazin-2-amine.126. A compound according to claim 3, named3,6-diethyl-2-(1-ethylpropoxy)-5-(2-methoxy-4,6-dimethylphenyl)pyrazine.127. A compound according to claim 3, named3,6-dimethyl-2-(1-ethylpropoxy)-5-(2,4-dichlorophenyl)pyrazine.
 128. Acompound according to claim 3, named3,6-diethyl-2-(1-ethylpropoxy)-5-(2-hydroxy-4,6-dimethylphenyl)pyrazine.129. A compound according to claim 3, named3,6-diethyl-2-(1-ethylpropoxy)-5-(2,4-dichlorophenyl)pyrazine.
 130. Acompound according to claim 3, named3,6-dimethyl-N-(1-methoxy-2-butyl)-5-(2,4-dimethoxyphenyl)pyrazin-2-amine.
 131. A compound according to claim 3, named2-(2,4-dichlorophenyl)-5-[2-(methoxymethyl)pyrrolidin-1-yl]-3,6-dimethylpyrazine.132. A compound according to claim 3, named2-(2,4-dimethoxyphenyl)-5-[2-(methoxymethyl)pyrrolidin-1-yl]-3,6-dimethylpyrazine.133. A compound according to claim 3, named3,6-dimethyl-N-(1-ethylpropyl)-5-(2-methyl-4-chlorophenyl)pyrazin-2-amine.134. A compound according to claim 3, named3,6-dimethyl-N-(1-ethylpropyl)-5-(2-trifluoromethyl-4-dimethylaminophenyl)pyrazin-2-amine.135. A compound according to claim 3, named3,6-diethyl-N-(1-ethylpropyl)-5-(2-trifluoromethoxy-4-methoxyphenyl)pyrazin-2-amine.136. A compound according to claim 3, named3,6-diethyl-N-(1-ethylpropyl)-5-(2-methoxy-4-trifluoromethylphenyl)pyrazin-2-amine.137. A compound according to claim 3, named3,6-diethyl-N-(1-ethylpropyl)-5-(2-trifluoromethyl-4-methoxyphenyl)pyrazin-2-amine.138. A compound according to claim 3, named3,6-diethyl-N-(1-ethylpropyl)-5-(2-methoxy-4-methylphenyl)pyrazin-2-amine.139. A compound according to claim 3, named3,6-diethyl-N-(1-methoxy-2-butyl)-5-(2-chloro-4-dimethylaminophenyl)pyrazin-2-amine.140. A compound according to claim 3, named3,6-diethyl-N-(1-methylpropyl)-5-(2-chloro-4-dimethylaminophenyl)pyrazin-2-amine.141. A compound according to claim 3, named3,6-diethyl-N-(2-methylpropyl)-5-(2-chloro-4-dimethylaminophenyl)pyrazin-2-amine.142. A compound according to claim 3, named3,6-diethyl-N-(2-phenylethyl)-5-(2-chloro-4-dimethylphenyl)pyrazin-2-amine.143. A compound according to claim 3, named3,6-diethyl-N-(1-propylbutyl)-5-(2-trifluoromethyl-4-dimethylaminophenyl)pyrazin-2-amine.
 144. A compound according to claim 3, named3,6-diethyl-N-(1-methoxy-2-butyl)-5-(2-trifluoromethyl-4-dimethylaminophenyl)pyrazin-2-amine.
 145. A compound according to claim 3, named2-(2,6-dimethoxy-4-chloro-phenyl)-6-ethyl-5-(1-ethylpropoxy)-3-methoxypyrazine.146. A compound named2-(2-methoxy-5-triflurormethoxyphenyl)-3-ethyl-6-methylamino-5-(1-ethylpropoxy)-pyrazine.147. A method for treating a CNS disorder or disease, comprisingadministering to a patient in need of such treatment between 0.1 to 140mg per kg body weight per day of a compound according to claim
 3. 148.The method of claim 147 wherein the CNS disorder or disease is ananxiety disorder, stress-related disorder, or eating disorder.
 149. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of a compound according to claim
 3. 150. Acompound according to claim 3 wherein, in a standard in vitro CRFreceptor binding assay the compound exhibits an IC₅₀ value less than orequal to 1 micromolar.
 151. A method for modulating CRF receptorfunction, comprising administering to a patient in need of suchmodulation an effective amount of a compound of according to claim 3.152. A method for treating a CNS disorder or disease, comprisingadministering to a patient in need of such treatment an effective amountof a compound according to claim
 3. 153. The method of claim 152 whereinthe CNS disorder or disease is an anxiety disorder, stress-relateddisorder, or eating disorder.
 154. A compound according to claim 3,wherein in a standard in vitro sodium channel functional assay thecompound does not show any statistically significant activity at thep<0.05 level of significance.
 155. A method of claim 152 wherein the CNSdisease or disorder is depression or a bipolar disorder.
 156. A methodof claim 152 wherein the CNS disease or disorder is anorexia nervosa,bulimia nervosa, or obesity.
 157. A method according to claim 152wherein in a standard in vitro CRF receptor binding assay the compoundexhibits an IC₅₀ value less than or equal to 1 micromolar.
 158. A methodaccording to claim 152 wherein in a standard in vitro CRF receptorbinding assay the compound exhibits an IC₅₀ value less than or equal to100 nanomolar.
 159. A method according to claim 152 wherein in astandard in vitro CRF receptor binding assay the compound exhibits anIC₅₀ value less than or equal to 10 nanomolar.
 160. A method accordingto claim 152 wherein the patient is a human.
 161. A method forlocalizing CRF receptors is tissue section samples comprising:contacting with a sample of tissue a deteactably-labelled compound ofclaim 3 under conditions that permit binding of the compound to CRFreceptors within the sample of tissue; washing the tissue sample toremove unbound compound; and detecting remaining bound compound.
 162. Apackaged pharmaceutical composition comprising a pharmaceuticalcomposition of claim 149 in a container and instructions for using thecomposition to treat a patient suffering from an anxiety disorder, astress-related disorder, or an eating disorder.